Molecular Pathways Controlling Autophagy in Pancreatic Cancer.

Maria New,Jun-Ichi Sakamaki,Jaclyn S Long,Sharon A Tooze,Tim Van Acker,Kevin M Ryan

doi:10.3389/fonc.2017.00028

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types where the 5-year survival rate shows no improvement.Despite conflicting evidence, the majority of data points to an essential role for autophagy in PDAC growth and survival, in particular constitutively activated autophagy, can provide crucial fuel to PDAC tumor cells in their nutrient-deprived environment.Autophagy, which is required for cell homeostasis, can both suppress and promote tumorigenesis and tumor survival in a context-dependent manner. Protein by protein, the mystery of how PDAC abuses the cell’s homeostasis system for its malignant growth has recently begun to be unraveled. In this review, we focus on how autophagy is responsible for growth and development of PDAC tumors and where autophagy and the mechanisms controlling it fit into PDAC metabolism. Understanding the range of pathways controlling autophagy and their interplay in PDAC could open the way for new therapeutic avenues.

Highlights

Pancreatic cancer is a disease in which malignant cells originate in pancreatic tissue, leading to over 200,000 deaths per year worldwide—making pancreatic cancer the ninth leading cause of death from cancer [1]
Treatment of pancreatic stellate cells (PSCs) with pancreatic ductal adenocarcinomas (PDACs)-conditioned medium significantly increased autophagic flux in PSCs and depletion of ATG5 and ATG7 in PSCs abolished alanine secretion. These findings reveal a two-way intra-tumor metabolic crosstalk in which PDAC signals to PSCs resulting in autophagy induction in the latter, followed by PSC-derived alanine secretion which can fuel the TCA cycle in PDAC
Within the PDAC cells, it is thought that autophagy is constitutively active and is regulated through transcriptional control [11] and reactive oxygen species (ROS)-related signaling [45]

Summary

INTRODUCTION

Pancreatic cancer is a disease in which malignant cells originate in pancreatic tissue, leading to over 200,000 deaths per year worldwide—making pancreatic cancer the ninth leading cause of death from cancer [1]. TP53 status has been shown to determine the role of autophagy in tumor development in mice KRAS mutant pancreatic tumors, where PDAC formation is accelerated by autophagy inhibition in cases where TP53 is absent [20] This may be because TP53-deficient tumors and cell lines have lower numbers of autophagosomes, so their viability is not dependent on the process [20]. Overriding MiT/TFE inactivation by mTORC1 via IPO8-driven nuclear import enables PDAC cells to maintain their intracellular amino acid pool by activation of both autophagy and lysosomal catabolism (Figure 2) [11] This system resembles the constitutive nuclear import of the pro-oncogenic protein eIF4E (a downstream target of mTORC1) in acute myeloid leukemia patients by IPO8 [66] and might be a general mechanism used by several cancer types. Autophagy inhibition by (3-MA, an inhibitor of PI3K, which blocks autophagosome formation) followed by PDAC treatment with U0126 or CAPE

Aim

Findings

CONCLUSION AND FUTURE DIRECTIONS