Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation

Abstract

Cancers acquire mutations in cooperating pathways that sustain their growth and survival. To support continued proliferation, tumor cells adapt their metabolism to balance energy production with their augmented biosynthetic needs. Although most normal differentiated cells use mitochondrial oxidative phosphorylation (OXPHOS) as the bioenergetic source, cancer cells have been proposed to rely principally on cytoplasmic glycolysis. The molecular basis for this shift, termed the Warburg effect, is the subject of intense investigation, because mechanistic understanding may lead to novel approaches to target the altered metabolism of cancer cells. Recently, mutations BRAF(V600E) have emerged as a major regulator of metabolic homeostasis. Melanoma cells may use a metabolic shift to circumvent BRAF(V600E)-induced senescence though limiting their reliance on OXPHOS and promote proliferation. Furthermore, BRAF(V600E) acts to suppress expression of the melanocyte master regulator microphthalmia-associated transcription factor (MITF) and the mitochondrial biogenesis coactivator PGC1α. Accordingly, therapeutic inhibition of BRAF(V600E) reverses metabolic reprogramming in melanoma cells and elevates OXPHOS through increased MITF-PGC1α levels. BRAF-targeted drugs modulate the metabolic state of malignant melanoma cells, and counteracting these adaptive responses using pharmacologic agents may prove useful in combinatorial therapeutic strategies. Clin Cancer Res; 20(9); 2257-63. ©2014 AACR.

Figure 1. Intersection of signaling, transcription and metabolism regulate generation of ATP and building block availability to sustain survival and growth, respectively

Growth factor mediated activation (EGF) of a receptor tyrosine kinase (EGFR) leads to downstream pathway signaling along the RAS-RAF-MEK-MAPK and PI3K-AKT-mTOR pathways. Key convergence points are MAPK mediated suppression of LKB1/AMPK energy sensing, and AKT activated translocation of the glucose transporter GLUT4 to the plasma membrane leading to augmented glucose import for anabolic (nucleotides, lipids, and amino acids) in addition to catabolism towards ATP regeneration in the mitochondria utilizing the proton gradient. Furthermore, MAPK stabilizes and mTOR increases translation of HIF1α, triggering the transcriptional function with effects on reducing pyruvate decarboxylation/oxidation to acetyl-CoA (Ac-CoA) destined for use in the TCA cycle. In melanoma cells, HIF1α activity reduces expression of MITF-PGC1α levels and thereby causes effects on reducing mitochondrial bioactivity (OXPHOS, ROS protection) in addition to differentiation associated cascades. Frequently mutant components (and pathways) in human cancers are indicted in red. Inhibitors of indicated pathway components are indicated in blue.