Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Lubna Therachiyil,Javeria Haroon,Michal Kulinski,Kodappully S. Siveen,Roopesh Krishnankutty,Joerg Buddenkotte,Shahab Uddin,Martin Steinhoff,Fairooz Sahir

doi:10.3389/fonc.2020.01744

Abstract

Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of TP53 gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type TP53 harboring HCT 116 and mutant TP53 harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.

Highlights

Colorectal cancer (CRC) is ranked as the third most commonly diagnosed cancer type after the lung and breast cancers worldwide beyond its geographical variations and localized temporal trends [1]
In order to assess cytotoxic effects of the drug OX on colon cancer cells in correlation to their p53 status, the wild-type p53 bearing HCT 116 cells and the mutant p53 bearing HT 29 cells were treated with OX (20 μM) and their cytotoxicity were measured by CCK8 assay after 24 and 48 h
The growth inhibition was significantly higher in wild-type p53-HCT 116 cells accounting to 70% after 48 h of OX treatment, while in mutant p53-HT 29 cells the growth inhibition accounted to only 40% (Figure 1A)

Summary

Introduction

Colorectal cancer (CRC) is ranked as the third most commonly diagnosed cancer type after the lung and breast cancers worldwide beyond its geographical variations and localized temporal trends [1]. Despite the advancements in pharmacokinetics with introduction of novel therapeutics, nearly half of the CRC patient population is reported to have the disease relapse [3, 4]. Chemoresistance, a feature by which the cancer cells become less sensitive to chemotherapeutic drugs forms one of the major reason for this disease relapse and pose a major challenge in cancer treatment regime [5]. Though mutations in several genes has been extensively correlated to CRC development, TP53 (p53) forms one of the most commonly mutated genes in cancer [7]. About 50% of CRC cases are known to pose this mutation [8]

Methods

Results

Conclusion