Dual inhibition of anti-apoptotic proteins BCL-XL and MCL-1 enhances cytotoxicity of Nasopharyngeal carcinoma cells

• Published in: Discover. Oncology 2022-02, Vol.13 (1), p.9-9, Article 9
• Main Authors: Abdul Rahman, Siti Fairus, Azlan, Azali, Lo, Kwok-Wai, Azzam, Ghows, Mohana-Kumaran, Nethia
• Format: Article
• Language: English
• Subjects: Apoptosis; BCL-XL; BFL-1; BH3 mimetics; Brief Communication; Cancer Research; Cell culture; Cell growth; Cloning; CRISPR; Cytotoxicity; Design; Gene expression; Genetic engineering; Internal Medicine; MCL-1; Medicine; Medicine & Public Health; Molecular Medicine; Nasopharyngeal carcinoma; Oncology; Proteins; Radiotherapy; Software; Spheroids; Surgical Oncology; Throat cancer
• ISSN: 2730-6011; 2730-6011
• DOI: 10.1007/s12672-022-00470-9

One of the many strategies that cancer cells evade death is through up-regulation of the BCL-2 anti-apoptotic proteins. Hence, these proteins have become attractive therapeutic targets. Given that different cell populations rely on different anti-apoptotic proteins for survival, it is crucial to determine which proteins are important for Nasopharyngeal carcinoma (NPC) cell survival. Here we determined the survival requirements for the NPC cells using a combination of the CRISPR/Cas9 technique and selective BH3-mimetics. A human apoptosis RT 2  Profiler PCR Array was first employed to profile the anti-apoptotic gene expressions in NPC cell lines HK-1 and C666-1. The HK-1 cells expressed all the anti-apoptotic genes ( MCL-1, BFL-1, BCL-2, BCL-XL, and BCL-w ). Similarly, the C666-1 cells expressed all the anti-apoptotic genes except BFL-1 (undetectable level). Notably, both cell lines highly expressed MCL-1 . Deletion of MCL-1 sensitized the NPC cells to BCL-XL selective inhibitor A-1331852, suggesting that MCL-1 and BCL-XL may be important for NPC cell survival. Co-inhibition of MCL-1 and BCL-2 with MCL-1 selective inhibitor S63845 and BCL-2 selective inhibitor ABT-199 inhibited NPC cell proliferation but the effect on cell viability was more profound with co-inhibition of MCL-1 and BCL-XL with S63845 and A-1331852, implying that MCL-1 and BCL-XL are crucial for NPC cell survival. Furthermore, co-inhibition of MCL-1 and BCL-XL inhibited the growth and invasion of NPC spheroids. Deletion of BFL-1 sensitized NPC cells to A-1331852 suggesting that BFL-1 may play a role in NPC cell survival. Taken together co-inhibition of BCL-XL and MCL-1/BFL-1 could be potential treatment strategies for NPC.