HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs

Abstract

Hypoxia-inducible factor 1 (HIF-1) has been associated with distant tumor metastasis; however, its function in multiple metastatic processes has not yet been fully elucidated. In the present study, we demonstrated that cancer cells transiently upregulated HIF-1 activity during their metastatic colonization after extravasation in the lungs in hypoxia-independent and reactive oxygen species (ROS)-dependent manners. Transient activation induced the expression of lactate dehydrogenase A and phosphorylation of the E1α subunit of pyruvate dehydrogenase, which indicated the reprogramming of glucose metabolic pathways from mitochondrial oxidative phosphorylation to anaerobic glycolysis and lactic acid fermentation. The administration of the HIF-1 inhibitor, YC-1, inhibited this reprogramming, increased intratumoral ROS levels, and eventually suppressed the formation of metastatic lung tumors. These results indicate that HIF-1-mediated metabolic reprogramming is responsible for the survival of metastatic cancers during their colonization in lungs by reducing cytotoxic ROS levels; therefore, its blockade by HIF-1-inhibitors is a rational strategy to prevent tumor metastasis.

Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

“…Several reports have shown that ROS mediates the stabilization of HIFα in hypoxic conditions [46][47][48] and destabilization in normoxic conditions [49][50][51]. ROS also stabilizes HIF1α in metastatic cancer cells, which in turn reprograms the cells by decreasing cytotoxic ROS levels, leading to further metastasis [52]. ROS is known to oxidize Fe +2 to Fe +3 ; this may lead to declined activity of PHDs and accumulation of HIF1α.…”

“…Circulating cancer cells recruited to the lungs demonstrate an increase in intracellular ROS levels that lead to HIF1α stability. The ROS-stabilized HIF1α shifts cell metabolism from aerobic to anaerobic glycolysis by phosphorylating pyruvate dehydrogenase E1 alpha subunit (PDH-E1α), inhibiting pyruvate dehydrogenase activity and increasing the expression of lactate dehydrogenase A (LDHA) [52]. This vicious cycle promotes tumor metastasis and growth.…”

Cancer, Oxidative Stress, and Metastasis

“…For example, HIF-1 activity is transiently increased during metastasis due to high ROS levels (Montagner et al 2012;Zhao et al 2014). HIF-1 activation metabolically reprograms metastasizing cells away from oxidative phosphorylation to glycolysis and lactic acid production, through increased expression of lactate dehydrogenase and pyruvate dehydrogenase.…”

Impaired mitophagy activates mtROS/HIF-1α interplay and increases cancer aggressiveness in gastric cancer cells under hypoxia

“…Lower levels of mitochondrial ROS (mtROS) play important roles as signaling molecules to adapt to stress and are required for normal cell homeostasis, while excessive quantities of mtROS directly damage proteins, lipids and nucleic acids, and lead to cell death (21). Previous reports have shown that HIF-1α is also stabilized by mtROS, whereby mtROS inactivate PHDs by decreasing intracellular Fe 2+ levels through oxidization to Fe 3+ (24)(25)(26)(27). Macroautophagy (general autophagy) is a dynamic process through which cytosol and organelles are sequestered into a double-membrane vesicle called an autophagosome and delivered to the lysosome for breakdown and recycling during challenging conditions, such as nutrient depletion or hypoxia.…”