Influence of mitochondrial DNA alterations on cisplatin chemoresistance in oral squamous cell carcinoma

Abstract

Event Abstract Back to Event Influence of mitochondrial DNA alterations on cisplatin chemoresistance in oral squamous cell carcinoma Amnani Aminuddin1, Pei Yuen Ng1, Chee-Onn Leong2, 3 and Eng Wee Chua1* 1 Drug and Herbal Research Centre, Faculty of Pharmacy, University Kebangsaan Malaysia, Malaysia 2 School of Pharmacy, International Medical University, Malaysia 3 Centre for Cancer and Stem Cell Research, International Medical University, Malaysia Background Cisplatin is a commonly used chemotherapeutic agent in the treatment of various solid tumours. To date, the development of secondary resistance towards cisplatin remains a major obstacle to the success of cancer chemotherapy including oral squamous cell carcinoma (OSCC). Recently, it has been reported that mitochondrial DNA (mtDNA) alterations could promote tumourigenesis and chemoresistance. Herein, we aimed to evaluate the genetic basis of cisplatin chemoresistance through comprehensive mtDNA profiling. Methods Cisplatin sensitivity of two OSCC cell lines, SAS and H103, and cancer stem-like cells (CSCs) derived from SAS were tested using the MTS assay. Variation in mtDNA abundance was measured by a real-time polymerase chain reaction (qPCR) assay. Sequencing of the mitochondrial genome was performed with the nanopore sequencing technology (MinION™) to screen for mtDNA point mutations. An in-house bioinformatics workflow was established for mutation discovery, and all detected mtDNA mutations were validated by Sanger sequencing. Results H103 was more cisplatin-resistant than SAS-CSCs and SAS. In keeping with the assessment of cisplatin sensitivity, qPCR analysis showed that mtDNA was less abundant in H103 than SAS-CSCs and SAS. Interestingly, the nanopore sequencing identified a mutation in the D310 (displacement loop) regions of both SAS-CSCs and SAS, but the mutation was absent in H103. The displacement loop is a non-coding region that regulates mtDNA replication and gene transcription. Conclusion We demonstrated that enhanced cisplatin resistance in H103 could be influenced by mtDNA abundance. The absence of an activating mutation in the displacement loop region could have accounted for the lower abundance of H103’s mitochondrial genome when compared with SAS-CSCs and SAS. We suggest that alterations in mtDNA abundance might be used as a marker of cisplatin responsiveness in the treatment of OSCC. Future work may focus on investigating the mechanisms that underpin variation in mtDNA content and therefore cisplatin response. Keywords: mitochondrial DNA, cisplatin resistance, Oxford Nanopore Technology, Mitochondrial DNA content, Point Mutation Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Poster Presentation Topic: Cancer Citation: Aminuddin A, Ng P, Leong C and Chua E (2019). Influence of mitochondrial DNA alterations on cisplatin chemoresistance in oral squamous cell carcinoma. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00106 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Eng Wee Chua, Drug and Herbal Research Centre, Faculty of Pharmacy, University Kebangsaan Malaysia, Kuala Lampur, Malaysia, cew85911@ukm.edu.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Amnani Aminuddin Pei Yuen Ng Chee-Onn Leong Eng Wee Chua Google Amnani Aminuddin Pei Yuen Ng Chee-Onn Leong Eng Wee Chua Google Scholar Amnani Aminuddin Pei Yuen Ng Chee-Onn Leong Eng Wee Chua PubMed Amnani Aminuddin Pei Yuen Ng Chee-Onn Leong Eng Wee Chua Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.