AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress

Abstract

Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease.

Benzylamine and Thenylamine Derived Drugs Induce Apoptosis and Reduce Proliferation, Migration and Metastasis Formation in Melanoma Cells

“…From a molecular point of view, F10503LO1 decreased the content of phospho-AKT, and phospho-AMPK, impaired angiogenesis through a decrease in the intratumor content of VEGF and decreased p53 levels suggesting a specific mechanism leading to a reduced in vivo viability of B16F10 cells and tumor dissemination. In addition, the observation that AMPK is dephosphorylated in samples of tumors treated with the drug probably contributes to cancer cell death due to the inability to provide energy substrates to the growing tumor ( 41 ). Interestingly, DTIC did not reproduce these effects, nor did it exhibit a significant synergism with F10503LO1 in terms of signaling or tumor growth arrest, prevailing the action of the benzylamine derivative over the DTIC treatment ( 5 , 21 ).…”

Is oxidative stress MYC’s Achilles heel?

“…However, treatment of MYC-deleted cells with 991, a highly selective pharmacological activator of AMPK [12], completely rescued both the elevated ROS and the cytotoxic effect of MYC deletion, mirroring the cytoprotective role of NUAK1 in counteracting ROS. Furthermore, as is the case for high expression of NUAK1 in CRC, high expression of AMPK in Melanoma correlates with significantly reduced overall survival of human patients [2,3].…”

“…A separate study by Radtke and colleagues has now revealed a similar role for AMPK, or rather, for a specific subset of AMPK complexes, in MYC-dependent Melanoma [3]. Although often discussed as though it were a single entity, the AMP-activated protein kinase is a trimeric complex comprised of 1 of 2α, 1 of 2β and 1 of 3γ subunits, and there is evidence that multiple distinct complexes can assemble and co-exist in cells, presumably responding to distinct cues and/or regulating specific downstream substrates [10].…”

“…De-regulated MYC perturbs many aspects of cell function but its influence on cellular metabolism may impart specific vulnerabilities that can be exploited for cancer therapy [1]. Two new studies shine the spotlight on oxidative stress as a specific vulnerability in MYC-dependent cancers and pinpoint NUAK1 and AMPK as key participants in how cancer cells cope with oxidative stress [2,3].…”

“…Suppression of MYC specifically reduced expression of both of these subunits, whereas the β1 and γ1 subunits were unaffected, providing the first evidence that MYC may selectively enrich for a specific subset of AMPK complexes. Significantly, depletion of either AMPKα1 or β2 resulted in pronounced apoptosis of MYC positive melanoma cells [3].…”