Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells

Nicola J. Mabjeesh, Dawn E. Post, Margaret T. Willard, Balveen Kaur, Erwin G. Van Meir, Jonathan W. Simons, Hua Zhong

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor composed of α and β subunits. HIF-1 is critically involved in cellular responses to hypoxia, glycolysis, and angiogenesis. Here, we show that treatment of prostate cancer PC-3 and LNCaP cells with the benzoquinone ansamycin geldanamycin, an Hsp90-specific inhibitor, induced degradation of HIF-1α protein in a dose- and time-dependent manner under both normoxia and hypoxia. This inhibition was also shown in other common cancer types tested. Rapid degradation of nuclear HIF-1α protein levels was accompanied by respective inhibition in HIF-1α functional transcription activity of VEGF. No difference between HIF-1α mRNA levels before or after geldanamycin treatment was found. Moreover, [35S]methionine pulse-chase analysis revealed that HIF-1α protein half-life was markedly decreased in the presence of geldanamycin compared with that in control. The geldanamycin-induced degradation of HIF-1α was reversed by proteosome inhibitors lactacystin and MG-132. We conclude that geldanamycin induces reduction of HIF-1α levels and its down-stream transcriptional activity by accelerating protein degradation independent of O2 tension. Thus, benzoquinone ansamycin drugs and their derivatives, such as 17-allyl-aminogeldanamycin, are excellent candidates as small molecule drug inhibitors of HIF-1 overexpression in cancer cells.

Original languageEnglish
Pages (from-to)2478-2482
Number of pages5
JournalCancer Research
Volume62
Issue number9
StatePublished - 1 May 2002
Externally publishedYes

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