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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00912

A Novel Drug Resistance Mechanism: Genetic loss of xeroderma pigmentosum complementation group C (XPC) enhances glycolysis-mediated drug resistance in DLD-1 colon cancer cells

  • 1State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China
  • 2Key Laboratory of Infectious Diseases Molecular Biology, Ministry of Education, Chongqing Medical University, China

The pro-apoptotic proteins BAX and BAK are critical regulatory factors constituting the apoptosis machinery. Downregulated expression of BAX and BAK in human colorectal cancer lead to chemotherapeutic failure and poor survival rate in patients. In this study, isogenic DLD-1 colon cancer cells and the BAX and BAK double knockout counterpart were used as the cellular model to investigate the role of BAX/BAK-associated signaling network and the corresponding downstream effects in the development of drug resistance. Our data suggested that DLD-1 colon cancer cells with BAX/BAK double-knockout were selectively resistant to a panel of FDA-approved drugs (27 out of 66), including etoposide. PCR array analysis for the transcriptional profiling of genes related to human cancer drug resistance validated the altered level of 12 genes (3 upregulated and 9 downregulated) in DLD-1 colon cancer cells lack of BAX and BAK expression. Amongst these genes, XPC responsible for DNA repairment and cellular respiration demonstrated the highest tolerance towards etoposide treatment accompanying upregulated glycolysis as revealed by metabolic stress assay in DLD-1 colon cancer cells deficient with XPC. Collectively, our findings provide insight into the search of novel therapeutic strategies and pharmacological targets to against cancer drug resistance genetically associated with BAX, BAK, and XPC, for improving the therapy of colorectal cancer via the glycolytic pathway.

Keywords: Bax, BAK, XPC, Glycolysis, drug-resistance, CRC (colorectal cancer)

Received: 08 Mar 2019; Accepted: 18 Jul 2019.

Edited by:

Christopher Gerner, University of Vienna, Austria

Reviewed by:

HEMLATA SUKHIJA, City of Hope National Medical Center, United States
Vishwa M. Khare, University of Pennsylvania, United States  

Copyright: © 2019 Han, Tang, Qu, Mok, Chen, He, Li, Zhang, Qiu, Liu, Law and Wong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Vincent Kam Wai Wong, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China, bowaiwong@gmail.com