Abstract
The perihydroxylated perylene quinone hypericin has been reported to possess potent anti-metastatic and antiangiogenic activities, generated by targeting diverse crossroads of cancer-promoting processes via unique mechanisms. Hypericin is the only known exogenous reagent that can induce forced poly-ubiquitination and accelerated degradation of heat shock protein 90 (Hsp90) in cancer cells. Hsp90 client proteins are thereby destabilized and rapidly degraded. Hsp70 client proteins may potentially be also affected via preventing formation of hsp90-hsp70 intermediate complexes. We show here that hypericin also induces enhanced degradation of hypoxia-inducible factor 1α (HIF-1α) in two human tumor cell lines, U87-MG glioblastoma and RCC-C2VHL−/− renal cell carcinoma and in the non-malignant ARPE19 retinal pigment epithelial cell line. The hypericin-accelerated turnover of HIF-1α, the regulatory precursor of the HIF-1 transcription factor which promotes hypoxic stress and angiogenic responses, overcomes the physiologic HIF-1α protein stabilization which occurs in hypoxic cells. The hypericin effect also eliminates the high HIF-1α levels expressed constitutively in the von-Hippel Lindau protein (pVHL)-deficient RCC-C2VHL−/− renal cell carcinoma cell line. Unlike the normal ubiquitin-proteasome pathway-dependent turnover of HIF-α proteins which occurs in normoxia, the hypericin-induced HIF-1α catabolism can occur independently of cellular oxygen levels or pVHL-promoted ubiquitin ligation of HIF-1α. It is mediated by lysosomal cathepsin-B enzymes with cathepsin-B activity being optimized in the cells through hypericin-mediated reduction in intracellular pH. Our findings suggest that hypericin may potentially be useful in preventing growth of tumors in which HIF-1α plays pivotal roles, and in pVHL ablated tumor cells such as renal cell carcinoma through elimination of elevated HIF-1α contents in these cells, scaling down the excessive angiogenesis which characterizes these tumors.
Highlights
Formation of tumor metastases by disseminating cancer cells and their explosive growth remains the most prevalent cause for cancer treatment failure and death
Forced hypoxia-inducible factor 1a (HIF-1a) degradation under hypoxia by cell treatment with hypericin Aiming to decipher the mechanism for the anti-angiogenic activity of hypericin [13], we examined whether hypericin affects HIF-1a adaptive stabilization, which occurs under hypoxia in the absence of proline and asparagine hydroxylation [1] in three human cell lines: U87-MG glioblastoma cells, RCC-C2VHL2/2 (C2VHL2/2) renal carcinoma cells deficient in pVHL, and ARPE19 retinal pigment epithelial cells
heat shock protein 90 (Hsp90) involvement is relevant to our analyses of antiangiogenic effects, because we previously reported in murine breast and squamous carcinoma tumor cells that hypericin induces hsp90 polyubiquitination and accelerated degradation, destabilizing and degrading hsp90-client proteins in these cells [14]
Summary
Formation of tumor metastases by disseminating cancer cells and their explosive growth remains the most prevalent cause for cancer treatment failure and death. The VEGFVEGFR2 complexes which form require association with hsp to activate the downstream signaling that initiates the neoangiogenic cascade, [4] and activates the integrin-focal adhesion kinase (FAK)-Src signaling complex Both FAK and Src are hsp client proteins, requiring association with this chaperone for maintaining their functional conformations [5,6]. These functions include formation of focal adhesions associated with an F-actin contractile apparatus that are linked to the cell membrane and activate the migration machinery via interaction with the extracellular matrix [7]. Hsp inhibition can disrupt several sites in angiogenic and cell dispersion signaling cascades and interfere with tumor progression
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