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Back to Journal »Cancer Management and Research» Volume 13

The role and mechanism of autophagy in pancreatic cancer: an updated review

Authors: Ma Jie, Xue Hua, He Lihua, Wang Li, Wang Xinjie, Li Xu, Zhang Li

Published on November 2, 2021, the 2021 volume: 13 pages 8231-8240

DOI https://doi.org/10.2147/CMAR.S328786

Single anonymous peer review

Editor who approved for publication: Dr. Sanjeev Srivastava

Ma Jian, 1– 3 Xue Huan, 1– 3 He Lihong, 1– 3 Wang Lingyun, 1– 3 Wang Xiaojuan, 1– 3 Li Xun, 1– 3 Zhang Lei 1– 3 1 General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu Province 730000; 2 Gansu Provincial Key Laboratory of Biotherapy and Regenerative Medicine Transformation, Lanzhou, Gansu, 730000; 3 First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, 730000 Corresponding author: Li Xun, Department of General Surgery, First Hospital of Lanzhou University, Gansu Province No. 1, Donggang West Road, Chengguan District, Lanzhou City, 730000 People’s Republic of China Tel 86 13993138612 Email [email protected] Zhang Lei Department of General Surgery, First Hospital of Lanzhou University Email [Email protection] Abstract: Pancreatic cancer has a high morbidity and high mortality rate, and is one of the most common malignant tumors in the world. Despite extensive research, the prognosis is still very poor. Autophagy is a lysosomal-mediated, highly conservative degradation process that can remove abnormal proteins and damaged organelles from the body, and is upregulated in pancreatic ductal adenocarcinoma. Based on differences in tumor microenvironment and tumor stage, autophagy has different roles in the pathophysiology and treatment of pancreatic cancer. In the initial stage, autophagy inhibits the transformation of precancerous lesions into cancer. However, in the progressive phase, autophagy promotes tumor growth. Autophagy is also one of the main mechanisms of drug resistance during treatment. Here, we describe the role of autophagy in the progression of pancreatic cancer and discuss related treatment strategies for this disease. Keywords: Pancreatic ductal adenocarcinoma, cell growth, migration, tumor microenvironment, treatment

Pancreatic ductal adenocarcinoma (PDAC) originates from malignant pancreatic acinar epithelial cells and is the most common pancreatic cancer. Globally, PDAC is the 12th most common malignant tumor and the 7th cause of cancer-related death, with a 5-year survival rate of only 9%. 1 PDAC metastasizes early and progresses rapidly; symptoms are irregular. PDAC is usually diagnosed in the middle or late stages of cancer. Therefore, most patients lose the opportunity of surgical resection, making chemotherapy the main treatment for PDAC. However, the frequent drug resistance of tumor cells makes advanced chemotherapy less effective than early chemotherapy. 2 The oncogene KRAS and the tumor suppressor gene TP53 are the most frequently changed genes in PDAC patients. Although a lot of research has been conducted on the therapeutic effects of KRAS pathway inhibitors, the results are not satisfactory. Therefore, it is necessary to further study the targeted therapy of PDAC.

Autophagy is a drug resistance mechanism in tumor therapy. It can promote cell survival in harsh environments, but unregulated autophagy can promote cell apoptosis. 4 Autophagy is divided into three types: macroautophagy, chaperone-mediated autophagy and microautophagy. 3 Macroautophagy (hereinafter referred to as autophagy) is the main autophagy process. It is activated during periods of cellular undernutrition and hypoxia, and after the encapsulated cargo is degraded, it provides metabolites to the cell.

Autophagy plays a complex role in tumor cells; studies have shown that autophagy can not only inhibit the onset of cancer, but also promote the growth of advanced tumors. 4 Increasing evidence shows that cancer cells are more dependent on autophagy than normal cells, and this dependence may be further strengthened during treatment. 5 More and more research groups are studying autophagy as a target for cancer treatment.

In this review, we introduced autophagy and focused on its role in the occurrence, development and treatment of pancreatic cancer. The research of autophagy is developing rapidly. The knowledge we have gained not only helps us understand the basic molecular mechanism of autophagy, but also provides a basis for clinical decision-making of targeted therapy related to autophagy.

Autophagy is a highly conservative cellular stress response. Dr. Yoshinori Ohsumi discovered the mechanism of using yeast to regulate autophagy. 6 Five events that initiate autophagy (Figure 1): (1) initiation, (2) double-membrane nucleation and phagocytic cell formation, (3) phagocytic cell extension and encapsulation targets for cytoplasmic degradation, (4) autophagy Fusion of body and lysosome to form autophagolysosome, and (5) degradation of autophagolysosome cargo. 7 Figure 1. Regulation of autophagy signaling pathway. Autophagy is a complex degradation process, including the following key steps: (A) initiation; (B) nucleation; (C) maturation; (D) fusion; (E) degradation. During startup, low ATP, hypoxia, and amino acid deficiency lead to AMPK activation or mTOR inhibition, and the formation of ULK complexes. The ER membrane ruptures to form phagocytes. Under starvation, JNK1-mediated phosphorylation of BCL2 is blocked. BECN1 separates from BCL2 to form a class III PI3K complex. The BECN1 in the class III PI3K complex interacts with ER and participates in double-membrane nucleation to form phagocytes, which contain abnormal proteins and damaged organelles. ATG5 binds to ATG12 and forms a complex with ATG16L, which is involved in the elongation of phagocytes. After LC3 is processed, it is inserted into expanded phagocytic cells to form mature autophagosomes. Then, autophagosomes fuse with lysosomes to form autophagolysosomes and degrade the contents. Abbreviations: AMPK, AMP-activated protein kinase; ATG, autophagy-related; TSC1/2, tuberous sclerosis complex subunit 1/2; MTORC1, the mechanism target of rapamycin complex 1; RB1CC, retinoblastoma Cell tumor 1 coiled coil; BCL, B-cell lymphoma 2; BECN1, Beclin1; AMBRA1, activating molecule in Beclin1 regulated autophagy; ER, endoplasmic reticulum; JNK1, c-Jun N-terminal kinase 1; VPS34, cyst Foam protein sorting 34; PIK3R4, phosphatidylinositol 3-kinase regulatory subunit 4; PIK3C3, phosphoinositide 3-kinase catalytic subunit 3; ULK, unc-51-like autophagy-activated kinase 1.

Figure 1 Regulation of autophagy signaling pathway. Autophagy is a complex degradation process, including the following key steps: (A) initiation; (B) nucleation; (C) maturation; (D) fusion; (E) degradation. During startup, low ATP, hypoxia, and amino acid deficiency lead to AMPK activation or mTOR inhibition, and the formation of ULK complexes. The ER membrane ruptures to form phagocytes. Under starvation, JNK1-mediated phosphorylation of BCL2 is blocked. BECN1 separates from BCL2 to form a class III PI3K complex. The BECN1 in the class III PI3K complex interacts with ER and participates in double-membrane nucleation to form phagocytes, which contain abnormal proteins and damaged organelles. ATG5 binds to ATG12 and forms a complex with ATG16L, which is involved in the elongation of phagocytes. After LC3 is processed, it is inserted into expanded phagocytic cells to form mature autophagosomes. Then, autophagosomes fuse with lysosomes to form autophagolysosomes and degrade the contents.

Abbreviations: AMPK, AMP-activated protein kinase; ATG, autophagy-related; TSC1/2, tuberous sclerosis complex subunit 1/2; MTORC1, the mechanism target of rapamycin complex 1; RB1CC, retinoblastoma Cell tumor 1 coiled coil; BCL, B-cell lymphoma 2; BECN1, Beclin1; AMBRA1, activating molecule in Beclin1 regulated autophagy; ER, endoplasmic reticulum; JNK1, c-Jun N-terminal kinase 1; VPS34, cyst Foam protein sorting 34; PIK3R4, phosphatidylinositol 3-kinase regulatory subunit 4; PIK3C3, phosphoinositide 3-kinase catalytic subunit 3; ULK, unc-51-like autophagy-activated kinase 1.

The mammalian target of rapamycin (mTORC1) is a serine-threonine kinase responsible for transducing autophagy signals; 8 mTORC1 binds and phosphorylates Unc-51-like kinase 1 (ULK1). When cells lack amino acids, ULK1 is dephosphorylated and initiates autophagy; under low ATP conditions, AMP-activated protein kinase (AMPK) promotes autophagy. 8 In addition, inhibited mTORC1 or activated AMPK can transduce the downstream pre-priming complex ULK1/2-Atg13-FIP200-Atg101 to initiate autophagy. 9

Class III phosphatidylinositol 3-kinase (PtdIns3K) complex nucleates autophagosomes; the complex includes phosphatidylinositol 3-kinase catalytic subunit type (3PIK3C3), phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4), Vesicle Protein Sorting 34 (VPS34), Beclin1 Regulates Autophagy Protein 1 (AMBRA1), Beclin1 (BECN1)1, and ATG14. BECN1 regulates the formation of the PtdIns3K complex during the assembly of phagocytes. B-cell lymphoma 2 (BCL2) prevents BECN1 from binding to VPS34 and inhibits autophagy. In the cell starvation state, JNK1-mediated phosphorylation of BCL2 is inhibited and promotes autophagy. 10 VPS34 combines with BECN1 to phosphorylate phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P). 11 PI3P recruits other ATG proteins and prolongs phagocytes. If any of these processes are inhibited, phagocytes will break down, thereby preventing autophagy.

Two ubiquitin-like (UBL) systems regulate the elongation of phagocytes through the E1-E2-E3 three-stage enzyme chain reaction: Atg12-Atg5 UBL and microtubule-associated light chain 3 B (LC3B)-phosphatidylethanolamine (PE) UBL12 .8 E1-like enzyme Atg7 and E2-like enzyme Atg10 form a covalent bond between Atg12 and Atg5. The Atg12-Atg5 conjugate recruits Atg16L1 to form a complex-Atg12-Atg5-Atg16L1, which functions as an E3-like enzyme of LC3B-PE UBL. LC3 is cleaved by the cysteine ​​protease ATG4B to produce LC3B-I. Then LC3B-1 binds to the glycine residue on PE. The diffusion form of LC3-I is converted to the lipidated form LC3-II by E1-like enzyme ATG7 and E2-like enzyme ATG3.

The LC3-II inserted into phagocytes elongated the membrane and formed a double-layer structure in the autophagosome. LC3 exists on the inner and outer surface membranes of autophagy and is recruited into phagocytes by Atg5-Atg12.10

Rab7 is a member of the Ras-related protein in the brain (Rab) family. 13 Rab7 interacts with homotype fusion and protein sorting (HOPS)/C type vacuolar protein sorting (Vps C type) complex to mediate membrane binding and fusion. 14 In addition, family M member 1 (PLEKHM1) containing the pleckstrin homology domain, the RAB7 effector, also binds to the components of the HOPS complex. PLEKHM1 interacts with LC3/GABARAP family proteins, which regulate the fusion of autophagosomes and lysosomes. 15 After the autophagosome is formed, it will degrade internally separated substances and 16 provide nutrients to cells to maintain homeostasis. However, the role of autophagy in PDAC remains to be further elucidated.

Histological and cytological studies have shown that when the pancreas suffers from intravascular pancreatic tumors (PanIN), autophagy increases. 17 In addition, PDAC cells have been shown to rely on autophagy for nutrients and energy to survive in vitro. 18 Here, we review the role of autophagy in the occurrence, development and treatment of PDAC.

PDAC is induced by a variety of factors, including inflammation, genetic mutations, and impaired mitochondrial function. Here, we review the role of autophagy in the onset of PDAC.

Autophagy regulates inflammation during the pathogenesis of PDAC. Studies have shown that knocking out autophagy-related genes (ATG5 or ATG7) or the protein encoding lysosomal function LAMP2 can cause severe acinar cell degeneration, pancreatic atrophy, fibrosis and inflammation. 19 ATG7-deficient mice were found to have reduced autophagy flux and increased endoplasmic reticulum stress, pancreatic cell degeneration, and acinar ductal metaplasia (ADM) formation compared to controls. 20 ADM is a precursor of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion of PDAC. 21 This indicates that autophagy inhibition increases the susceptibility of patients to PDAC.

The mutation of Kirsten rat sarcoma virus oncogene is the main cause of PDAC. 22 When the oncogene KRAS is activated, the metabolic demands of pancreatic cells increase. Overexpressed vacuolar membrane protein 1 (VMP1) interacts with BECN1 and promotes autophagy of pancreatic cells to provide nutrients for cell metabolism. 23 It was found that the administration of autophagy inhibitor chlorquinine can effectively reverse the overexpression of VMP1 and induce the formation of PanIN in Pdx1-Cre; KrasG12D; vmp1 mouse.23

In addition, 75% of human PDAC cells have P53 deletion. 22 Rosenfeldt et al.24 found that in PDAC cells driven by KRAS mutations, autophagy has both cancer-promoting and tumor-inhibiting effects, depending on the presence of the P53 gene. They also found that KARS mice lacking ATG5 or ATG7 developed low-grade peripancreatic lesions without developing high-grade PanIN and PDAC. In contrast, in mice with oncogenic KRAS and P53 deletions, the pathogenesis of PDAC is accelerated. However, Yang et al. 25 demonstrated that chloroquine treatment or RNAi inhibited autophagy to inhibit the growth of PDAC cells independently of P53.

The different results may be related to Rosenfeldt's use of the P53 homozygous deletion model. The pancreas of these mice developed without functional P53, which is different from the gradual progression from PanIN to PDAC in other models and humans. In human PDAC cells, usually only one P53 allele is deleted. In addition, inhibition of autophagy can prevent oncogenic KARS mutations from progressing to PDAC. 25 Therefore, according to the above studies, manipulation of autophagy to treat PDAC may depend on the KRAS oncogene status.

Compared with normal cells, PDAC cells have a higher degree of mitochondrial destruction. 26 Maintaining healthy mitochondria (both quantity and quality) is essential for cell homeostasis. As a result, mitochondrial autophagy in PDAC cells increases and selectively degrades damaged mitochondria. Mitophagy is regulated by PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PRKN/PARK2) and BCL2 interacting protein 3 (BNIP3L/NIX). 26 Xie et al. showed that PINK1/PRKN defects will accelerate the occurrence of PDAC. 26 However, KRAS-mediated overexpression of BNIP3L can increase the glucose metabolism and antioxidant capacity of cells, and promote the occurrence of PDAC (Figure 2). 26 Figure 2 The role of autophagy regulators in pancreatic tumorigenesis in KRAS mutant mice. Abbreviations: ATG, autophagy-related; VMP1, vacuolar membrane protein 1; BNIP3L, BCL2 interacting protein 3-like; PINK, PTEN-inducing kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; TP53, tumor protein p53.

Figure 2 The role of autophagy regulators in pancreatic tumorigenesis in KRAS mutant mice.

Abbreviations: ATG, autophagy-related; VMP1, vacuolar membrane protein 1; BNIP3L, BCL2 interacting protein 3-like; PINK, PTEN-inducing kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; TP53, tumor protein p53.

In short, autophagy can inhibit the pathogenesis of PDAC, but it can provide energy for cells. When pancreatic cells have oncogenic KRAS mutations, it promotes the occurrence of PDAC.

Autophagy promotes disease by regulating cell proliferation, invasion, migration, metabolism and immune escape. Studies have shown that the use of autophagy inhibitor chloroquine or shRNA to inhibit ATG5 and ATG7 can inhibit the growth of human PDAC cell lines and reduce tumor mass in PDAC mouse models. 17 We discussed the subsequent part of the complex regulatory network of autophagy and its role in the development of PDAC.

An important feature of PDAC is that the fibrosis of the extracellular matrix increases with the progress of PDAC, 27 resulting in low tumor blood vessel density, severe hypoxia, and limited nutrient access. Therefore, cancer cells activate pancreatic stellate cells (PSC), increase the expression of autophagy proteins, and secrete non-essential amino acids (NEAA), such as alanine, to meet the metabolic needs of cancer cell growth. 27 In addition, increased autophagy causes PSC to change from a dormant state to an active state. Activated PSC secretes extracellular matrix (ECM) proteins and cytokines to increase the aggressiveness of tumors. 28 It is closely related to the short survival of PDAC patients. The administration of autophagy inhibitors to PSC can reduce the production of ECM proteins and cytokines, and reduce the proliferation and invasiveness of mouse PDAC cells. 28 This suggests that autophagy can promote PDAC progression by regulating non-tumor cells.

PDAC cells are characterized by imbalanced proliferation and the ability to invade surrounding tissues, which are responsible for poor prognosis and high mortality. Gorgulu et al. 29 showed that tumor cell proliferation and migration increased in ATG5-deficient PDAC mice. However, in these mice, tumor formation was prevented. Interestingly, knocking out ATG5 in pancreatic cancer cell lines increased their proliferation and migration. In human PDAC samples, lower ATG5 expression levels are associated with tumor migration and shorter patient survival time. This suggests that the expression level of ATG5 should be considered when using autophagy inhibitors to treat PDAC to avoid drug resistance.

Transforming growth factor-β (TGF-β) promotes the proliferation, invasion and migration of advanced tumors. 30 He et al.30 found that TGF-β can affect the expression of TFEB in SMAD4-positive PDAC cells, thereby promoting TFEB-mediated autophagy. TFEB-mediated increase in autophagy is negatively correlated with the prognosis of PDAC patients. Chen et al. 31 found that the effect of TGF-β-induced autophagy on the proliferation and invasiveness of PDAC depends on the expression of SMAD4. TGF-β-induced autophagy enhanced the migration of SMAD4-negative PDAC cells and inhibited cell growth, while the opposite effect was observed in SMAD4-positive PDAC cells. This indicates that different genetic backgrounds may have different effects on autophagy in PDAC.

Ubiquitin-like protein 4A (UBL4A) can act on lysosomal-associated membrane protein 1 (LAMP1) to inhibit autophagy, thereby inhibiting PDAC cell proliferation and metastasis. 32 High UBL4A expression in PDAC is associated with a good prognosis and prolonged patient survival. 33 RNA-binding protein QKI can activate the proliferation, invasion and metastasis of surrounding fibroblasts, and increase the autophagy of PDAC cells. 33 In addition, MAPK can affect the interaction between PDAC and matrix and induce autophagy, thereby increasing the proliferation, invasion and migration of PDAC cells. 34 These results indicate that autophagy in the tumor microenvironment may promote the invasion and migration of PDAC cells.

The low blood vessel density during PDAC leads to severe hypoxia and limited nutrient utilization. Therefore, PDAC cells must change their metabolic pathways to maintain immortal proliferation. As mentioned above, changes in mTORC1 activity and enhancement of AMPK signal transduction will increase autophagy during cell starvation. In addition, TEFB overexpression can regulate the expression of Ras-related GTP-binding D (RagD), promote the recruitment of mTORC1 to lysosomes, and promote tumor growth. 35 TFEB stabilizes lysosomes and supports the nutritional requirements of PDAC cell proliferation, which is essential for maintaining tumor growth. 35 Therefore, there is a complex relationship between autophagy and PDAC metabolism that can be used to develop new therapies for PDAC. We focused on the regulatory mechanism of autophagy in glucose metabolism, amino acid metabolism and oxidative stress (Figure 3). Figure 3 Autophagy maintains the metabolism and function of PDAC cells. The autophagy pathway is regulated by different metabolic conditions (such as oxidative stress, low glucose and low amino acids), in which cellular components are degraded. In this process, bioenergy intermediates are reused to promote cell survival. Abbreviations: AGER, advanced glycosylation end product specific receptor; AMPK, AMP activated protein kinase; BECN1, beclin 1; GPX1, glutathione peroxidase 1; HMGB1, high mobility group box 1; mTOR, Lei Mechanical target of Pamycin; PKM2, the M2 splice isoform of PKM (pyruvate kinase M1/2); PDAC, pancreatic ductal adenocarcinoma; pink, PTEN-inducible kinase 1; PRKN, parkin RBR E3 ubiquitin protein linkage Enzyme; ROS, reactive oxygen species; SREBF1, sterol regulatory element binding transcription factor 1; ULK1, unc-51-like autophagy activated kinase 1.

Figure 3 Autophagy maintains the metabolism and function of PDAC cells. The autophagy pathway is regulated by different metabolic conditions (such as oxidative stress, low glucose and low amino acids) in which cellular components are degraded. In this process, bioenergy intermediates are reused to promote cell survival.

Abbreviations: AGER, specific receptor for advanced glycosylation end products; AMPK, AMP activated protein kinase; BECN1, beclin 1; GPX1, glutathione peroxidase 1; HMGB1, high mobility group box 1; mTOR, Lei The mechanical target of Pamycin; PKM2, the M2 splice isoform of PKM (pyruvate kinase M1/2); PDAC, pancreatic ductal adenocarcinoma; pink, PTEN-inducible kinase 1; PRKN, parkin RBR E3 ubiquitin protein linkage Enzyme; ROS, reactive oxygen species; SREBF1, sterol regulatory element binding transcription factor 1; ULK1, unc-51-like autophagy activated kinase 1.

Glucose is an important nutrient of PDAC. Under aerobic conditions, PDAC uses aerobic glycolysis to produce lactic acid instead of oxidative phosphorylation (OXPHOS). 36 When PDAC cells lack glucose, they produce large amounts of ROS to activate autophagy and the supply needed for growth. 37 In contrast, glutathione peroxidase 1 (GPX1) inhibits autophagy by reducing the production of ROS, making PDAC cells susceptible to hanger-induced cell death. 38 Although this finding indicates that GPX1 acts as an autophagy inhibitor in PDAC, the role of other members of the GPX family in PDAC remains unknown. Pyruvate kinase M2 (PKM2) is an important regulator of glycolysis and is down-regulated in PDAC cells with low glucose levels; however, in PDAC cells with reduced glucose, low PKM2 expression up-regulates AMPKα1 expression and induces autophagy to promote cell survival . 39 Bryant et al. found that KRAS and MAPK inhibition increased autophagy flux in KRAS mouse models and human PDAC cells and drove PDAC to become acutely dependent on autophagy. 40,41 Therefore, the combined inhibition of KRAS and autophagy may play an important role in the treatment of PDAC. 40

In PDAC cells, reprogramming energy metabolism plays an important role in cell proliferation and tumor growth. We discussed glucose metabolism above, but recently amino acid metabolism, especially the reprogramming of glutamine metabolism in PDAC cells, has attracted a lot of research interest.

Autophagy provides glutamine to PDAC cells through micropinocytosis. 39 Glutamine is broken down into ammonia and glutamate in the mitochondria. The latter is transformed into TCA cycle intermediates α-ketoglutarate (α-KG) and DMKG42, which can promote the growth of PDAC. Therefore, autophagy provides glutamine for PDAC cells and promotes the growth of PDAC. 43 However, in PDAC cells, α-KG can activate mTORC1 to reduce autophagy. 44 When chronic mTORC1 inhibition results in amino acid deficiency, TFEB expression increases to activate autophagy. This indicates that there is a dynamic balance between glutamine metabolism and autophagy to ensure the growth of PDAC cells.

Branched Chain Amino Acids (BCAA) Leucine, Isoleucine, and Valine are three essential amino acids (EAA). They cannot be synthesized in cells and must be obtained from the diet. 42 Interestingly, leucine is an mTORC1 agonist that can promote the growth of PDAC. Solute carrier family 38 member 9 (SLC38A9) transports leucine from the lysosome into the cytoplasm. Wyant et al.45 found that in cells lacking SLC38A9, lysosomal leucine levels remained essentially unchanged, even though the leucine levels in whole cells were reduced compared to the control. This indicates that the leucine utilization of PDAC cells depends on the interaction between autophagy and lysosomal proteolysis.

PSC in the tumor microenvironment also affects autophagy and amino acid metabolism in PDAC. PDAC cells induce PSC autophagy to provide alanine. 27 Alanine can be converted into pyruvate to provide a carbon source for the TCA cycle or promote lipid biosynthesis and synthesis of non-essential amino acids, such as serine and glycine. Therefore, the interaction between autophagy induced by cancer cells and PCS supports the metabolic requirements of PDAC cells and promotes tumor growth. During the progress of PDAC, cells are under oxidative stress. Tumor cells will produce a large amount of ROS, which can damage DNA and accelerate the development of PDAC. Elevated ROS levels can inhibit mTORC1 and activate autophagy. 46 High mobility group box 1 (HMGB1) is a new type of BECN1 binding protein expressed during autophagy. 47 In PDAC cells, the induction of autophagy depends on the redox state of HMGB1. When HMGB1 is reduced, it binds to the receptor for advanced glycation end products (RAGE), induces BECN1-dependent autophagy, and promotes the survival of pancreatic tumor cell lines. 48 The zinc chelator TPEN can damage the mitochondrial function of PDAC cells and cause oxidative stress. At the same time, TPEN inhibits lysosomal activity and inhibits autophagy, leading to apoptosis of PDAC cells. 49 In summary, there is a complex relationship between oxidative stress, ROS, and autophagy.

We describe the complex relationship between autophagy and PDAC metabolism, and the potential to combine metabolic pathway manipulation and autophagy to treat PDAC in the future. However, the specific regulation mechanism between autophagy and metabolism of PDAC needs further study.

Yang et al. established a PDAC mouse model expressing AtG4BC47A to inhibit autophagy and found that the tumor’s macrophage infiltration increased and partially mediated tumor regression. 50 This indicates that autophagy is an immune response of PDAC cells. In addition, in PDAC cells, major histocompatibility complex class I (MHC-1) can present endogenous antigens to CD8 T cells to recognize cancer cells for destruction. 51

Interestingly, compared with human pancreatic ductal epithelial (HPDE) cells, PDAC cells express low levels of MHC-1, but are highly enriched in autophagy-related autophagosomes and lysosomes. 52 This NBR1-mediated autophagy MHC-1 degradation increases and antigenicity increases 51 This will weaken antigen presentation and promote tumor immune evasion. However, after autophagy is inhibited, the expression of MHC-1 in PDAC cells is restored, which promotes the proliferation and activation of CD8 T cells, and enhances the cytotoxicity of tumor cells in vivo and in vitro. 52 In addition, after inhibiting autophagy, MDSCs, CD4 T cells and CD103 DCs also changed, but their specific role in PDAC remains unclear. 52 Therefore, the relationship between autophagy and PDAC cellular immune response will be the focus of future research.

PDAC is difficult to cure and often relapses. At present, the main treatment methods are surgery, chemotherapy and radiotherapy. However, frequent drug resistance in PDAC is the main cause of poor treatment outcomes for patients. This may be because autophagy helps tumor cells cope with various stresses, including hypoxia, low pH and reduced nutrient supply. Therefore, understanding the mechanism of autophagy is essential to improve PDAC treatment.

At present, the gold standard for PDAC chemotherapy is to combine FOLFIRINOX and albumin-bound paclitaxel with gemcitabine. 53 Some studies have found that increased autophagy may be the cause of resistance to chemotherapy drugs. Gemcitabine and 5-fluorouracil induce apoptosis and increase autophagy. 54,55 The combination of chloroquine and gemcitabine or 5-fluorouracil can significantly inhibit tumor growth. 55 At the same time, AMPK inhibition can enhance the toxicity of gemcitabine or 5-fluorouracil to tumors. 54 Clinical studies have also shown that gemcitabine combined with hydroxychloroquine is more effective than gemcitabine alone. 56

SMAD4 gene depletion induces autophagy by increasing ROS levels. 57 SMAD4 depleted PDAC cells are resistant to radiotherapy, and it has been found that this resistance can be reversed by the administration of autophagy inhibitors. 57 This suggests that autophagy plays a role in the resistance of PDAC cells to radiotherapy.

In a recent study, inhibition of KRAS-RAF-MEK-ERK signal transduction increased autophagy. 40 After ERK inhibition, tumor cells increasingly rely on autophagy for nutrition. In addition, after the administration of the combination of ERK inhibitor trametinib and chloroquine, the development of PDAC in vivo and in vitro was significantly affected. 40 In pancreatic cancer cell lines, cell mortality was found to be increased by administering a combination of trametinib and chloroquine, compared to chloroquine alone. After the implementation of this treatment regimen, the grafts of MIA-PaCa2 xenograft mice showed degeneration. A patient with metastatic pancreatic cancer who did not respond to all standard treatment regimens had tumor markers cancer antigen 19-9 (CA19-9) and Overall tumor burden. 58 These results provide evidence for a new combination regimen for the treatment of PDAC, indicating that autophagy plays an important role in the treatment of pancreatic cancer.

Autophagy plays an important role in the success of PDAC treatment. Preclinical studies of PDAC targeted autophagy therapy have achieved gratifying results. However, the results of clinical studies were disappointing. Therefore, maximizing the role of autophagy in the treatment of pancreatic cancer patients is a challenge for future research.

In the past decade, with the discovery of new regulatory networks and transduction pathways, the understanding of the mechanism of autophagy has continued to deepen. The pathophysiological role of autophagy in cancer, especially pancreatic cancer, has also been explored. Changes in autophagy play an important role in the occurrence and development of pancreatic cancer. This is not only reflected in cancer cells, but also in non-cancer cells in the tumor microenvironment. In addition, the autophagy function in PDAC is regulated by oncogenes (such as KRAS) and tumor suppressor genes (such as TP53).

Autophagy plays a complex role in cancer, and our current knowledge is still very limited. Benign lesions in autophagy-deficient mice were prevented from transforming into pancreatic cancer. Since autophagy provides nutrition for the growth of pancreatic cancer, this finding in autophagy-deficient mice indicates that the autophagy process can be an effective intervention target for the prevention and treatment of pancreatic cancer.

The targeted autophagy treatment of pancreatic cancer has achieved great success in preclinical research, but its clinical application in humans has produced disappointing results. This difference may be due to the following reasons. First, our understanding of the specific role of autophagy at the molecular level and how it affects tumors is currently very limited. Second, the mouse model cannot accurately replicate the pathology of human pancreatic cancer. Finally, autophagy is critical to cell homeostasis, and the systemic application of autophagy inhibitors may interfere with its normal function in tissues.

Autophagy is considered to be a mechanism by which tumor cells maintain their high levels of metabolism in a nutrient-deficient environment. Autophagy also helps tumor cells respond to multiple stresses (ie, hypoxia, low pH, and reduced nutrient supply). Inhibiting autophagy may be an important direction for targeted therapy of pancreatic cancer in the future, and the development and application of autophagy inhibitors should be the focus. In particular, designing such autophagy inhibitors that do not penetrate the blood-brain barrier can reduce neurotoxicity. In addition, it is important to develop inhibitors that do not affect autophagy of non-cancer cells around pancreatic cancer, but do affect tumor cell growth and reduce the ability of cancer cells to metastasize.

Because genetic changes can affect autophagy, it is important to collect tumor or blood samples from PDAC patients to assess the dependence of pancreatic cancer cells on autophagy before treatment with autophagy inhibitors. Autophagy inhibition has a positive effect only when the tumor changes. Clinically, autophagy inhibitors should be used in patients diagnosed with pancreatic cancer. In addition, because autophagy inhibitors are used systemically, researchers should consider the long-term potential toxic effects on normal cells and tissues when developing and applying drugs. In short, exploring the mechanism of autophagy inhibitors and elucidating their interaction with other anti-tumor drugs in pancreatic cancer will provide new methods and ideas for the clinical treatment of pancreatic cancer.

PDAC, pancreatic ductal adenocarcinoma; mTORC1, mammalian target of rapamycin complex 1; ULK1, Unc-51-like kinase 1; AMPK, AMP-activated protein kinase; PtdIns3K, class III phosphatidylinositol 3-kinase; PIK3C3 , Phosphatidylinositol 3-kinase catalytic subunit type 3; VPS34, vesicle protein sorting 34; AMBRA1, Beclin1 regulated autophagy protein 1 activating molecule; BCL2, B-cell lymphoma 2; PI3P, 3-phosphate Phosphatidylinositol; UBL, two ubiquitin-like; LC3B, light chain 3B; PE, phosphatidylethanolamine; PanIN, pancreatic tumor; ADM, acinar ductal metaplasia; PSCs, pancreatic stellate cells; NEAA, non-essential amino acids ; OXPHOS, oxidative phosphorylation; MHC-1, major histocompatibility complex class I; CA19-9, cancer antigen 19-9.

Thanks for the English editor of Editage (www.editage.cn).

All authors have made significant contributions to the concept and design, data acquisition or data analysis and interpretation; participated in drafting articles or critically revised important knowledge content; agreed to submit to the current journal; finally approved the version to be published; and agreed Responsible for all aspects of work.

This research was funded by the Gansu Provincial Higher Education Innovation Fund Project (2021B-013), the National Undergraduate Innovation and Entrepreneurship Talent Training Program (202110730198), and the Gansu Provincial Natural Science Foundation (21JR7RA369).

The authors report no conflicts of interest related to this work.

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