Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells.
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.
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.
Heather G
HG
Hambright
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, California, 94710, USA.
Peng
P
Meng
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|South Texas Veterans Health Care System, San Antonio, Texas, 78229, USA.
Addanki P
AP
Kumar
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA.
Rita
R
Ghosh
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010936:Plant Extracts / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D005978:Glutathione; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C512605:Nexrutine; C546842:MTOR protein, human
NexrutineR; mTORC1; melanoma; oxidative stress; reactive oxygen species