Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells

Abstract

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.

Epigenetics Reactivation of Nrf2 in Prostate TRAMP C1 Cells by Curcumin Analogue FN1

“…55 Oxidative stress and chronic inflammation, and chronic exposure to carcinogens and mutagens are crucial in the initiation of carcinogenesis. 56 Nrf2 pathway protects against oxidative stress and thus prevents carcinogenesis.…”

Autophagy: In the cROSshairs of cancer

“…We define ROS threshold as a window of redox cycling which a cell can sustain, without affecting or triggering cell death mechanisms. We have recently demonstrated that human melanoma cells have an elevated oxidative stress phenotype compared with melanocytes, and that disrupting the melanoma cell oxidative stress ‘threshold’ perturbs PI3K/AKT/mTOR oncogenic signaling required for survival, and culminates in cell death [20]. Clinical efforts that seek to modulate redox disruption in melanoma patients are reinforced by multiple studies showing increased serum levels of oxidative stress markers (malondialdehyde; MDA, oxidized protein products, SOD activity etc.)…”

Induction of apoptosis by ethanol extract of <i>Citrus unshiu</i> Markovich peel in human bladder cancer T24 cells through ROS-mediated inactivation of the PI3K/Akt pathway

“…Interestingly, many previous studies show that increased production of ROS and inactivation of the PI3K/Akt signal pathway are related to the induction of cancer cell apoptosis (20)(21)(22). Although studies on the role of ROS production in PI3K/ Akt inactivation have not been fully understood, ROSdependent PI3K/Akt signaling pathway blockade may be a potential therapeutic target for inducing apoptosis in cancer cells (23,24).…”