Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor–mediated upregulation of caveolin-1

Abstract

Caveolin-1 (CAV1) is an essential structural constituent of caveolae, specialized lipid raft microdomains on the cell membrane involved in endocytosis and signal transduction, which are inexplicably deregulated and are associated with aggressiveness in numerous cancers. Here we identify CAV1 as a direct transcriptional target of oxygenlabile hypoxia-inducible factor 1 and 2 that accentuates the formation of caveolae, leading to increased dimerization of EGF receptor within the confined surface area of caveolae and its subsequent phosphorylation in the absence of ligand. Hypoxia-inducible factordependent up-regulation of CAV1 enhanced the oncogenic potential of tumor cells by increasing the cell proliferative, migratory, and invasive capacities. These results support a concept in which a crisis in oxygen availability or a tumor exhibiting hypoxic signature triggers caveolae formation that bypasses the requirement for ligand engagement to initiate receptor activation and the critical downstream adaptive signaling during a period when ligands required to activate these receptors are limited or are not yet available.

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

“…This occurs at the plasma membrane in a ligand-independent manner in hypoxia. 42 Therefore, we measured the protein level of CAV1 of A549 cells over a 72-h time course and found that CAV1 protein level decreased over time in hypoxia by up to 83% (Fig. 9A), which is consistent with the change in tyrosine phosphorylation of EGFR ( Fig.…”

“…[21][22][23][24][25] Hypoxia can either promote tumor growth by stimulating the expression of cell survival proteins such as EGFR and antiapoptotic BCL2 family members or inhibit tumor growth by upregulating the expression of cell death proteins such as BNIP3, BAX (BCL2-associated X protein) and BID (BH3 interacting domain death agonist). 25,41,42,55 Furthermore, hypoxia can induce autophagy that has been reported to either inhibit or promote cell death creating a dilemma for developing strategies to kill hypoxic cancer cells. [27][28][29][30][31][32][33][34][35][36][37][38] We found that growth factors might be one of the key factors influencing the function of autophagy in hypoxia by regulating the level of autophagic flux.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Apart of this mechanism, Wang et al showed caveolin-1 (CAV1) to promote ligandindependent activation of EGFR in hypoxic ccRCC cells [86]. CAV1 is a major structural component of caveolae, which are specialized lipid raft microdomains on the cell membrane [87].…”

“…Under hypoxia, the formation of caveolae increases and some fraction of EGFR in the fluid of cell membrane milieu localizes there. The substantially smaller surface area of caveolae relative to the plasma membrane permits ligandindependent activation of EGFR [86]. This mechanism bypasses the requirement for ligand engagement to initiate receptor activation when ligand availability may be limited [86].…”

“…Increased expression potentially mediated by HIF-1α [130,168] Non-small cell lung cancer (NSCLC), RCC, breast cancer, prostate cancer, glioblastoma cells EGFR mRNA translation through activated HIF-2α [76,79] 786-0 ccRCC cells EGFR Delayed receptor endocytosis [81] 786-O ccRCC EGFR Ligand-independent activation through elevated expression of CAV1 [86] T-47D and MDA-MB-468 breast cancer cells, HEK293 human embryonic kidney cells…”