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.