Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma.

Mathew Perez-Neut,Vidhya Rao,Lauren Haar,Sreevidya Santha,Saverio Gentile,Basabi Rana,Katherine Lansu,Walter K Jones

doi:10.18632/oncotarget.7831

Abstract

Ion channels play a major factor in maintaining cellular homeostasis but very little is known about the role of these proteins in cancer biology. In this work we have discovered that, the Kv11.3 (hERG3) a plasma-membrane potassium channel plays a critical role in the regulation of autophagy in a cancer cell model. We have found that pharmacologic stimulation of the Kv11.3 channel with a small molecule activator, NS1643 induced autophagy via activation of an AMPK-dependent signaling pathway in melanoma cell line. In addition, we have found that NS1643 produced a strong inhibition of cell proliferation by activating a cellular senescence program. Furthermore, inhibition of autophagy via siRNA targeting AMPK or treatment with hydroxychloroquine an autophagy inhibitor activates apoptosis in NS1643-treated cells. Thus, we propose that, Kv11.3 is a novel mediator of autophagy, autophagy can be a survival mechanism contributing to cellular senescence, and that use of a combinatorial pharmacologic approach of Kv11.3 activator with inhibitors of autophagy represents a novel therapeutic approach against melanoma.

Highlights

Autophagy is a ubiquitous lysosomal-dependent catabolic mechanism in which organelles or proteins are degraded [1]
In our previous work we found that pharmacological stimulation of a VGKC that is similar to Kv11.3 determines a strong inhibition of proliferation in breast cancer cells [28].In this work, we provide evidence that use of a small molecule Kv11.3 potassium ion channel activator, NS1643 determines autophagy in a B-RAF-dependent melanoma cell line without any significant effects in non-transformed skin cells
It has been shown that Kv11.1 channel, normally encoded by the human ether-a-go-go related gene 1 in heart [29], is critical in regulating cell proliferation of different cancer cell types and we found that stimulation of Kv11.1 with the pan-Kv11 activator NS1643 produced a significant inhibition of cancer cell proliferation

Summary

Introduction

Autophagy is a ubiquitous lysosomal-dependent catabolic mechanism in which organelles (macro/microautophagy) or proteins (chaperon-mediated autophagy) are degraded [1]. Autophagy can function as a survival mechanism to support replenishment of primary biomolecules that are crucial for cellular growth but it can activate a cell death pathway. The role of autophagy in cell biology is still controversial and it appears to be specific to the cellular context or pathological condition [2]. Autophagy progresses by formation of membranous structures called autophagosomes that recruit the Light Chain 3 (LC3-I) protein which is subsequently cleaved at the carboxy terminus (LC3-II) [5]. LC3-II remains on mature autophagosomes until fusion with lysosomes is completed (autophagolysosome) and it is used to monitor progression of autophagy process [6]. The content inside the autophagolysosome is degraded to simple biomolecules

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Conclusion