Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer

Jianjun Qi,Yidan Zhou,Bin Lu,Changliang Shan,Qin Chen,Liyi Li,Ting Chen,Ningning Zhou,Shouyong Mo,Yao Deng

doi:10.1038/s41419-020-02779-1

Abstract

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and is the second cause of cancerrelated death worldwide[1,2]
Inducing cancer cell death by promoting apoptosis has been proposed as an effective therapeutic approach for cancer therapy[29]
Under certain circumstances, unfolded and/or misfolded proteins can accumulate within endoplasmic reticulum (ER) due to the limitation of the degradation capabilities of proteasomes, which leads to the activation of ER stress and UPRER to promote cell survival[31,32]

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and is the second cause of cancerrelated death worldwide[1,2]. Chemotherapy combined with radiation therapy is the main treatment strategies used for advanced CRC. (1H)-pyridinone) is a broad-spectrum hydroxypyridonebased synthetic topical antifungal with anti-inflammatory effects[4]. CPX was widely used as an antifungal agent for decades and has been used as CPX olamine, the olamine (2-aminoethanol) salt of CPX5. CPX has recently been identified as a potential anticancer agent for a variety of cancers[6,7,8,9]. CPX was found to inhibit rhabdomyosarcoma by inhibiting mTORC1 signaling through the activation of the AMPK pathway[10]. CPX has an antileukemic and -neuroblastic effect by inhibiting β-Catenin and c-Myc signaling[11,12].

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Results

Conclusion