Autophagy in pancreatic cancer pathogenesis and treatment

Abstract

Pancreatic cancer is the fourth most common cancer to cause death due to advanced stage at diagnosis and poor response to current treatment. Autophagy is the lysosome-mediated degradation pathway which plays a critical role in cellular defense, quality control, and energy metabolism. Targeting autophagy is now an exciting field for translational cancer research, as autophagy dysfunction is among the hallmarks of cancer. Pancreatic tumors have elevated autophagy under basal conditions when compared with other epithelial cancers. This review describes our current understanding of the interaction between autophagy and pancreatic cancer development, including risk factors (e.g., pancreatitis, smoking, and alcohol use), tumor microenvironment (e.g., hypoxia and stromal cells), and molecular biology (e.g., K-Ras and p53) of pancreatic cancer. The importance of the HMGB1-RAGE pathway in regulation of autophagy and pancreatic cancer is also presented. Finally, we describe current studies involving autophagy inhibition using either pharmacological inhibitors (e.g., chloroquine) or RNA interference of essential autophagy genes that regulate chemotherapy sensitivity in pancreatic cancer. Summarily, autophagy plays multiple roles in the regulation of pancreatic cancer pathogenesis and treatment, although the exact mechanisms remain unknown.

Keywords: AMPK; Autophagy; HIF1α; HMGB1; RAGE; hypoxia; oncogene; p53; pancreatic cancer; pancreatitis.

Figure 1

Progression model for pancreatic ductal adenocarcinoma. PDAC progresses from PanINs. The progression from histologically normal ductal epithelium to low-grade PanIN to high-grade PanIN is associated with the accumulation of specific genetic changes. Early changes include K-ras mutations; intermediate changes include INK4A/p16 mutations; and changes associated with either in situ or early invasive cancer include p53, BRCA2, and DPC4/SMAD4. Elevated expression of autophagy in cancer cells has been implicated in the development of PDAC.

Figure 2

Autophagy and apoptosis: process and function. Autophagy and apoptosis may be triggered by common stimuli. As programmed cell survival, autophagy is an intracellular bulk degradation system, through which cytoplasmic component is delivered to lysosomes to be degraded. The main process of autophagy includes formation and maturation of the phagophore, autophagosome, and autolysosome. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing to LC3-II and can be degraded by autolysosome after binding adaptor protein p62. Autophagy provides amino acids and fatty acids for the synthesis of protein and ATP. In contrast, apoptosis is programmed cell death. There are two main pathways to control apoptosis. The extrinsic pathway is mediated by death receptors such as Fas/CD95. The intrinsic mitochondrial pathway is controlled by Bcl-2 family proteins such as Bax and other regulators, such as p53. Caspase 3 is a caspase protein that is activated by caspase 8 and caspase 9, and in turn, mediates substrate cleavage and cell destruction.

Figure 3

Pathways of autophagy induction by hypoxia and mutant RAS. (A) During hypoxia, autophagy is activated by sensors that detect low oxygen, unfolded proteins, and energy depletion. Low oxygen induces autophagy involving the HIF1α-mediated up-regulation of BNIP3 and BNIP3L. They compete with Bcl-2 for interaction with Beclin 1, and orient Beclin 1 to autophagosomes. AMPK is a major regulator of energy homeostasis. The kinase is sensitive to the AMP/ATP ratio: binding of AMP activates AMPK and induces phosphorylation by the tumor suppressor LKB1. Activation of AMPK inhibits mTOR-dependent signaling. Inhibition of mTOR induces autophagy. In addition, autophagy may be induced during hypoxia as a result of signals generated by the PERK-ATF4 mediated unfolded protein response in the endoplasmic reticulum. (B) The induction of autophagy by oncogenes such as mutant Ras is importance in tumorigenesis. Ras mutant activates the ROS-dependent JNK signaling pathway and upregulates the Atg5 gene to induce autophagy. Under certain circumstances, Ras mutant activates the MEK/ERK signaling pathway and upregulates the Beclin1 gene to induce autophagic cell death.

Figure 4

Pathways of autophagy induction by HMGB1 and RAGE. HMGB1 is an autophagy sensor in oxidative stress. HMGB1 plays important intranuclear, cytosolic, and extracellular roles in the regulation of autophagy. Nuclear HMGB1 regulates HSPB1 expression, which is required for the dynamic of mitophagy to control mitochondrial quality. Cytosolic HMGB1 is a Beclin1 binding protein. HMGB1-Beclin1 complex is a downstream signal from ULK1 complex. Interaction between HMGB1 and p53 regulates the level of HMGB1-Beclin1 complex. Loss of p53 promotes HMGB1 cytosolic translocation and increased HMGB1-Beclin1 complex and autophagy. In contrast, loss of HMGB1 promotes p53 cytosolic translocation and inhibits autophagy. Exogenous HMGB1 binds RAGE to active autophagy. ROS such as H₂O₂ increase activity of NF-κB and subsequently result in RAGE overexpression. This RAGE upregulation protects pancreatic tumor cells against oxidative injury and increases drug resistance by increasing Beclin1 dependent autophagy and decreasing apoptosis. In addition, RAGE is required for IL-6-induced phosporation of STAT3 (pSTAT3) and subsequently, autophagy induction.