DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1.

Rajesh Sharma,Robert C. Bast,Kwangkook Lee,Joshua P. Gray,Lan Pang,Weiqun Mao,Xiaowen Liang,Philip J. Rask,Margie N. Sutton,Amy M. Hurwitz,Timothy Palzkill,Steven W. Millward,Zhen Lu,Gilbert Y. Huang,Albert S. Reger,Choel Kim

doi:10.3390/cancers11040557

Abstract

Autophagy can protect cancer cells from acute starvation and enhance resistance to chemotherapy. Previously, we reported that autophagy plays a critical role in the survival of dormant, drug resistant ovarian cancer cells using human xenograft models and correlated the up-regulation of autophagy and DIRAS3 expression in clinical samples obtained during “second look” operations. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kD GTPase with homology to RAS that inhibits cancer cell proliferation and motility. Re-expression of DIRAS3 in ovarian cancer xenografts also induces dormancy and autophagy. DIRAS3 can bind to Beclin1 forming the Autophagy Initiation Complex that triggers autophagosome formation. Both the N-terminus of DIRAS3 (residues 15–33) and the switch II region of DIRAS3 (residues 93–107) interact directly with BECN1. We have identified an autophagy-inhibiting peptide based on the switch II region of DIRAS3 linked to Tat peptide that is taken up by ovarian cancer cells, binds Beclin1 and inhibits starvation-induced DIRAS3-mediated autophagy.

Highlights

Despite progress in surgery and chemotherapy, ovarian cancer, which affects more than22,000 women in the United States each year, still proves lethal in 70% of cases [1]
We have previously shown that the small GTPase DIRAS3 can induce autophagy and plays an important role in forming the autophagosome initiation complex (AIC) with Beclin1
The DIRAS3 and BECN1 interaction is essential for the formation of the autophagosome initiation complex (AIC) and for the development of autophagic vesicles, and became the focus of our interaction-derived peptide development [11]

Summary

Introduction

Despite progress in surgery and chemotherapy, ovarian cancer, which affects more than22,000 women in the United States each year, still proves lethal in 70% of cases [1]. Despite progress in surgery and chemotherapy, ovarian cancer, which affects more than. Metastatic, drug resistant ovarian cancer cells can remain dormant for years after treatment, only to grow progressively and kill patients. A catabolic process by which long-lived proteins and organelles are degraded into amino acids and fatty acids for catabolism and anabolism, has been shown to sustain dormant cancer cells and enhance resistance to paclitaxel and poly ADP ribose polymerase (PARP) inhibitors [2,3]. Cancers 2019, 11, 557 chloroquine can delay their subsequent outgrowth when dormancy is broken [5]. Autophagy can enhance resistance to paclitaxel, a critical component of primary chemotherapy for ovarian cancer [6,7]

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Conclusion