Tricistronic expression of MOAP-1, Bax and RASSF1A in cancer cells enhances chemo-sensitization that requires BH3L domain of MOAP-1

Lee, Yong Hoi * and Pang, Siew Wai * and Lechtich, E. R. and Shah, Khalid and Simon, S. E. * and Ponnusamy, S. and Narayanan, R. and Poh, Chit Laa * and Tan, Kuan Onn * (2020) Tricistronic expression of MOAP-1, Bax and RASSF1A in cancer cells enhances chemo-sensitization that requires BH3L domain of MOAP-1. Journal of Cancer Research and Clinical Oncology, 146 (7). pp. 1751-1764. ISSN 0171-5216

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Malihe Tricistronic expression of MOAP1 Bax and RASSF1A in cancer cells.pdf - Accepted Version
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Official URL: http://doi.org/10.1007/s00432-020-03231-9

Abstract

Purpose Although important for apoptosis, the signaling pathway involving MOAP-1(Modulator of Apoptosis 1), RASSF1A (RAS association domain family 1A), and Bax (Bcl-2 associated X protein) is likely to be dysfunctional in many types of human cancers due to mechanisms associated with gene mutation and DNA hyper-methylation. The purpose of the present study was to assess the potential impact of generating physiologically relevant signaling pathway mediated by MOAP-1, Bax, and RASSF1A (MBR) in cancer cells and chemo-drug resistant cancer cells. Methods The tricistronic expression construct that encodes MOAP-1, Bax, and RASSF1A (MBR) or its mutant, MOAP1∆BH3L, Bax and RASSF1A (MBRX) was expressed from an IRES (Internal Ribosome Entry Site)-based tricistronic expression vector in human breast cancer cells, including MCF-7, MCF-7-CR (cisplatin resistant) and triple negative breast cancer cells, BMET05, for functional characterization through in vitro and in vivo models. Results Transient expression of MBR potently promoted dose-dependent apoptotic signaling and chemo-sensitization in the cancer cells, as evidenced by loss of cell viability, nuclei condensation and Annexin-V positive staining while stable expression of MBR in MCF-7 cells significantly reduced the number of MBR stable clone by 86% and the stable clone exhibited robust chemo-drug sensitivity. In contrast, MBRX stable clone exhibited chemo-drug resistance while transiently over-expressed MOAP-1ΔBH3L inhibited the apoptotic activity of MBR. Moreover, the spheroids derived from the MBR stable clone displayed enhanced chemo-sensitivity and apoptotic activity. In mouse xenograft model, the tumors derived from MBR stable clone showed relatively high level of tumor growth retardation associated with the increase in apoptotic activity, leading to the decreases in both tumor weight and volume. Conclusions Expression of MBR in cancer cells induces apoptotic cell death with enhanced chemo-sensitization requiring the BH3L domain of MOAP-1. In animal model, the expression of MBR significantly reduces the growth of tumors, suggesting that MBR is a potent apoptotic sensitizer with potential therapeutic benefits for cancer treatment.

Item Type: Article
Uncontrolled Keywords: Tricistronic expression; MBR (MOAP-1); Bax; RASSF1A; Apoptosis; Chemo-resistant cancer; Animal model
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QR Microbiology
Divisions: Others > Non Sunway Academics
Sunway University > School of Science and Technology > Dept. Biological Sciences
Sunway University > School of Science and Technology > Centre for Virus and Vaccine Research
Depositing User: Dr Janaki Sinnasamy
Related URLs:
Date Deposited: 03 Jun 2020 03:21
Last Modified: 03 Jun 2020 03:21
URI: http://eprints.sunway.edu.my/id/eprint/1301

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