Squalene deters drivers of RCC disease progression beyond VHL status
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ORIGINAL ARTICLE
Squalene deters drivers of RCC disease progression beyond VHL status Karthikeyan Rajamani & Somasundaram S. Thirugnanasambandan & Chidambaram Natesan & Sethupathy Subramaniam & Balasubramanian Thangavel & Natarajan Aravindan
Received: 4 May 2020 / Accepted: 26 October 2020 # Springer Nature B.V. 2020
Abstract Identifying drug candidates to target cellular events/signaling that evades von Hippel-Lindau tumor suppressor (VHL) gene interaction is critical for the cure of renal cell carcinoma (RCC). Recently, we
Highlights • Seaweed-derived squalene inhibits RCC cell survival and prompts DNA fragmentation and apoptosis. • Squalene targets HIFs expression and HIF targets independent of the VHL status of the RCC cells. • Squalene regulates mitochondrial ROS and lipid peroxidation and targets inflammatory signaling while prompting apoptotic machinery. • Squalene exerted anti-genotoxic and anti-clastogenic effects in RCC cells and, together, could serve as a promising drug candidate for RCC treatment. K. Rajamani : S. S. Thirugnanasambandan : B. Thangavel Centre of Advanced Study in Marine Biology, Annamalai University, Parangipettai 608502 TN, India K. Rajamani : C. Natesan : S. Subramaniam Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar, Chidambaram 608002 TN, India K. Rajamani (*) WHO Collaborating Center for Occupational and Environmental Health, ICMR Center for Air Quality, Climate and Health, Department of Environmental Health Engineering, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, TN 600116, India e-mail: [email protected] N. Aravindan (*) Department of Radiation Oncology, University of Oklahoma Health Sciences Center, BMSB 737, 947 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA e-mail: [email protected]
characterized a triterpene-squalene derived from marine brown alga. Herein, we investigated the potential of squalene in targeting HIF-signaling and other drivers of RCC progression. Squalene inhibited cell proliferation, induced cell dealth and reverted the cells' metastatic state (migration, clonal expansion) independent of their VHL status. Near-identical inhibition of HIF-1α and HIF-2α and the regulation of downstream targets in VHL wild type and mutant cell lines demonstrated squalene efficacy beyond VHL-HIF interaction. In a rat model of chemically induced RCC, squalene displayed chemopreventive capabilities by substantial reversal of lipid peroxidation, mitochondrial redox regulation, maintaining Δψm, inflammation [Akt, nuclear factor κB (NF-κB)], angiogenesis (VEGFα), metastasis [matrix metalloproteinase 2 (MMP-2)], and survival (Bax/ Bcl2, cytochrome-c, Casp3). Squalene restored glutathione, glutathione reductase, glutathione-s-transferase, catalase, and superoxide dismutase and stabilized alkaline phosphatase, alkaline transaminase, and aspartate transaminase. The correlation of thiobarbituric acid reactive substance with VEGF/NF-κB and negative association of GSH with Casp3 show that squalene employs reduction in
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