The molecular mechanisms of chemoresistance in cancers.

Hua-Chuan Zheng

doi:10.18632/oncotarget.19048

Abstract

Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome. Their cross-talk frequently appears, such as the regulatory effects of EGFR-Akt-NF-κB signal pathway on the transcription of Bcl-2, Bcl-xL and survivin or EMT-related stemness. It is essential for the realization of the target, individualized and combine therapy to clarify these molecular mechanisms, explore the therapy target, screen chemosensitive population, and determine the efficacy of chemoreagents by cell culture and orthotopic model.

Highlights

Chemoresistance causes disease relapse and metastasis, challenges the improvement of clinical outcome for the cancer patients, and remains the main obstacle to cancer therapy
This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-кB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelialmesenchymal transition (EMT), cancer stemness, and exosome
Nanog overexpression directly resulted in EMT of ovarian cancer cells with a low susceptibility to cisplatin by activating Stat3 pathway and up-regulating the expression of multidrug resistance (MDR)-1 and GST-π [91, 92]

Summary

INTRODUCTION

Chemoresistance causes disease relapse and metastasis, challenges the improvement of clinical outcome for the cancer patients, and remains the main obstacle to cancer therapy. Cisplatin treatment increases p53 expression, which transcriptionally targets MDM2, p21Waf1/Cip and membrane Fas. p53 significantly down-regulates survivin in lung cancer cells by binding to the promoter of survivin for transcriptional suppression, which causes Caspase-3 activation and a decline in cell proliferation with response to adriamycin [9]. CD44v6 overexpression mediated the acquired chemoresistance to 5-FU and oxaliplatin by inducing autophagy and EMT, and activating both PI3KAkt and Ras-Erk signal pathways in colon cancer cells [82]. Nanog overexpression directly resulted in EMT of ovarian cancer cells with a low susceptibility to cisplatin by activating Stat pathway and up-regulating the expression of MDR-1 and GST-π [91, 92]. MSC exosomes were reported to induce 5-FU resistance of gastric cancer cells to by antagonizing 5-FU-induced apoptosis, activating CaM-Ks/Raf/MEK/ Erk pathway, and promoting MDR, MRP and LRP expression [121]. Zhang et al [125] found that β-elemene- induced exosomes reversed drug resistance of breast cancer by increasing PTEN expression and decreasing Pg-p expression in cells and exosomes

CONCLUSIONS AND PERSPECTIVE

There is cross-talk between these proteins