STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth.

Jingjing Gong,Amanda R Muñoz,Daniel Chan,Addanki P Kumar,Rita Ghosh

doi:10.18632/oncotarget.1810

Abstract

The dismal 5-year survival (<5%) for pancreatic cancer (PanCA) underscores the need for developing effective therapeutic options. Recent studies from our laboratory have shown that Nexrutine® (Nx), a bark extract from Phellodendron amurense exhibits excellent anticancer activity in human pancreatic cancer cells through inhibition of inflammatory signaling via STAT3/NFκB/Cox-2. Given the apparent high oxidative stress and autophagic activity in pancreatic tumors, we investigated the potential of Nx to modulate autophagy, reactive oxygen species (ROS), and their crosstalk. Our results show that Nx inhibits autophagy and decreases ROS generation. Pharmacological inhibition of autophagy led to decreased ROS generation and proliferation with no significant effect on apoptosis. Further, using combination index analysis we also found that combination of late-stage autophagy inhibitor with Nx exhibited a moderate synergistic to additive effect. Additionally, genetic or pharmacological inactivation of STAT3 reduced LC3-II levels and expression indicating a possible role for STAT3 in transcriptional regulation of autophagy. Since both inflammatory and oxidative stress signaling activate STAT3, our data implicates that STAT3 plays a vital role in the regulation of autophagy through its contributions to the positive feedback loop between ROS and autophagy. Overall, our findings reveal an important role for STAT3/LC3/ROS in Nx-mediated anti-pancreatic cancer effects.

Highlights

Autophagy is a dynamic multistep process in which essential autophagy genes (Atg) participate in forming double-membrane phagophores that engulf damaged cellular proteins, lipids, and organelles before delivering them to lysosomes for subsequent degradation[1,2,3]
We previously reported that Nx inhibits proliferation of pancreatic cancer cells [24]
Due to this unique characteristic feature and given that both autophagy induction and inhibition could be associated with cell death; we investigated the effect of Nx on autophagy

Summary

Introduction

Autophagy is a dynamic multistep process in which essential autophagy genes (Atg) participate in forming double-membrane phagophores that engulf damaged cellular proteins, lipids, and organelles before delivering them to lysosomes for subsequent degradation[1,2,3]. It can be induced in response to a variety of stimuli including nutrient limitation, oxidative stress, hypoxia, metabolic demands, endoplasmic reticulum stress, physiological agents, inflammatory and immunological signaling to protect cells from stress. Autophagy contributes to cellular homeostasis by removing damaged organelles and maintaining their normal turnover[4, 5]. The role of autophagy in carcinogenesis is complex with reports demonstrating functions in tumor promotion and suppression as well as a contribution to therapeutic resistance[6,7,8]. Tamoxifen induces apoptosis in human breast cancer cells through autophagy and endoplasmic reticulum stress[10, 11]. Compared to other cancer types such as lung and breast, a higher basal level of autophagy is observed in pancreatic cancer cells and in later stages of pancreatic tumor development[12]

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