MiR-204 reduces cisplatin resistance in non-small cell lung cancer through suppression of the caveolin-1/AKT/Bad pathway.

Gang Huang,Lu Li,Tianzheng Lou,Zaiting Ye,Jiongwei Pan,Wei Cheng,Zhangyong Yin,Zhuo Cao

doi:10.18632/aging.101907

Abstract

Non-small cell lung cancer (NSCLC) is the most common and lethal human malignant tumor worldwide. Platinum-based chemotherapy is still the mainstay of treatment for NSCLC. However, long-term chemotherapy usually induces serious drug resistance in NSCLC cells. Accordingly, treatment strategies that reverse the resistance of NSCLC cells against platinum-based drugs may have considerable clinical value. In the present study, we observed significant upregulation of CAV-1 expression and a significant decrease of miR-204 expression in cisplatin-resistant A549 (CR-A549) and cisplatin-resistant PC9 (CR-PC9) cells compared to their parental A549 and PC9 cells. Furthermore, we demonstrated that the downregulation of miR-204 expression was responsible for CAV-1 overexpression in these cisplatin-resistant NSCLC cells. We then found that enforced expression of miR-204 can resensitize CR-A549 and CR-PC9 cells to cisplatin-induced mitochondrial apoptosis through suppression of the caveolin-1/AKT/Bad pathway. We demonstrated that dysregulation of miR-204/caveolin-1 axis is an important mechanism for NSCLC cells to develop the chemoresistance.

Highlights

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide
We demonstrated that dysregulation of miR‐204/caveolin‐1 axis is an important mechanism for Non‐small cell lung cancer (NSCLC) cells to develop the chemoresistance
Upregulation of CAV-1 is essential for cisplatin resistance in NSCLC

Summary

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Platinum-based chemotherapy remains a widely used first-line strategy for the treatment of NSCLC. The clinical response to platinum-based chemotherapy is limited because NSCLC cells usually develop resistance after www.aging‐us.com the repeated use of platinum-based drugs. Cisplatin is the most commonly used platinum-based chemotherapeutic drug, and it exhibits effective and broad-spectrum anti-tumor activity against multiple cancers, including NSCLC [5, 6]. As a platinum-based drug, cisplatin can cross-link with DNA and subsequently inhibit DNA replication and transcription and trigger the apoptosis pathway in NSCLC cells [7]. Under the long-term use of cisplatin, cancer cells usually develop severe chemoresistance, which has become a major obstacle for the clinical use of cisplatin in patients with NSCLC [8,9,10]. Attenuation of the acquired chemoresistance to cisplatin in NSCLC treatment is an important clinical objective

Methods

Results

Conclusion