A Lactate-Induced Response to Hypoxia

Abstract

Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

“…In addition, several lines of evidence suggest that enzymes and metabolites that are involved in glycolysis also function as signaling molecules Ho et al, 2015;Lee et al, 2015;Luo et al, 2011;Yang et al, 2011). For instance, lactate promotes angiogenesis by activating the Raf-ERK pathway under hypoxic conditions in cancer cells (Lee et al, 2015).…”

“…In addition, several lines of evidence suggest that enzymes and metabolites that are involved in glycolysis also function as signaling molecules Ho et al, 2015;Lee et al, 2015;Luo et al, 2011;Yang et al, 2011). For instance, lactate promotes angiogenesis by activating the Raf-ERK pathway under hypoxic conditions in cancer cells (Lee et al, 2015). The Lin28 genes act as gatekeepers between stemness and differentiation via regulation of both early proliferative cell fates and later differentiating cell fates (Faas et al, 2013;Polesskaya et al, 2007;Tsialikas and RomerSeibert, 2015;Vadla et al, 2012;Yu et al, 2007).…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…The mTOR pathway, which is activated in response to hypoxia, likely plays a key role in immune cell activity during inflammation (95). Acidosis, which is a feature of the inflammatory microenvironment, is a known regulator of the hypoxic response (96) Indeed, lactate, which is produced during anaerobic respiration, has recently been reported to induce a hypoxic response independent of HIF, via NMYC downstreamregulated gene 2 (NDRG2) and Raf/ERK signaling (97).…”

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

“…More recently, Loo et al [7] documented that metastatic colorectal cancer cells rely on extracellular metabolite creatine to facilitate metastasis and cancer progression. Moreover, in addition to early reports that established lactate recycling as a significant fuel source for cancer progression [8,9], a most recent study showed that accumulated lactate facilitates hypoxia signaling to stimulate cancer growth [10]. Together, these significant findings all point to an alarming possibility that multiple seemingly wasteful metabolites are fuels for cancer cells, leaving it wide open for exploring potential alternative nutrients for tumors to shape up a comprehensive picture on cancer metabolism.…”