Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells
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Heather G. Hambright1, Peng Meng1,6, Addanki P. Kumar1,2,3,4,5, Rita Ghosh1,2,3,4
1Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
2Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
3Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
4Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA
5South Texas Veterans Health Care System, San Antonio, Texas, 78229, USA
6Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, California, 94710, USA
Rita Ghosh, e-mail: firstname.lastname@example.org
Keywords: Reactive oxygen species, oxidative stress, mTORC1, melanoma, NexrutineR
Received: December 22, 2014 Accepted: January 09, 2015 Published: January 29, 2015
Elevated oxidative stress in cancer cells contributes to hyperactive proliferation and enhanced survival, which can be exploited using agents that increase reactive oxygen species (ROS) beyond a threshold level. Here we show that melanoma cells exhibit an oxidative stress phenotype compared with normal melanocytes, as evidenced by increased total cellular ROS, KEAP1/NRF2 pathway activity, protein damage, and elevated oxidized glutathione. Our overall objective was to test whether augmenting this high oxidative stress level in melanoma cells would inhibit their dependence on oncogenic PI3K/AKT/mTOR-mediated survival. We report that NexrutineR augmented the constitutively elevated oxidative stress markers in melanoma cells, which was abrogated by N-acetyl cysteine (NAC) pre-treatment. NexrutineR disrupted growth homeostasis by inhibiting proliferation, survival, and colony formation in melanoma cells without affecting melanocyte cell viability. Increased oxidative stress in melanoma cells inhibited PI3K/AKT/mTOR pathway through disruption of mTORC1 formation and phosphorylation of downstream targets p70S6K, 4EBP1 and rpS6. NAC pre-treatment reversed inhibition of mTORC1 targets, demonstrating a ROS-dependent mechanism. Overall, our results illustrate the importance of disruption of the intrinsically high oxidative stress in melanoma cells to selectively inhibit their survival mediated by PI3K/AKT/mTOR.
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