Human hormone-refractory prostate cancers can harbor mutations in the O 2 -dependent degradation domain of hypoxia inducible factor-1α (HIF-1α)

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Abstract
Purpose. Androgen ablation, the preferred therapy for advanced prostate cancer, reduces blood flow and induces hypoxia in androgen-dependent tissues. Given the transient effectiveness of this therapy, we must consider whether a hypoxia-resistance mechanism might be involved in the development of therapeutic resistance by prostate cancer cells. The transcription factor protein, hypoxia-inducible factor 1α (HIF-1α), helps increase the expression of gene products that enable cells to survive conditions of hypoxic stress. Enhanced HIF-1α expression during hypoxia results from a drastic reduction of its degradation rate within a critical region of the protein referred to as the "oxygen-dependent degradation (ODD) domain". We sequenced HIF-1α cDNAs amplified from human prostate cancer cell lines and from hormone resistant prostate cancer specimens to determine whether prostate cancer cells might harbor mutations within the HIF-1α ODD domain. Methods. HIF-1α cDNAs were RT-PCR amplified from three prostate cancer cell lines (LNCaP, PC-3, and DU145), from five different human hormone-resistant prostate cancers and one normal prostate, all microdissected, and were sequenced to determine whether the HIF-1α gene products were wildtype or mutant. One specimen containing a hormone-resistant prostate tumor that expressed a mutated HIF-1α cDNA was further microdissected into benign and tumorous regions and DNAs extracted from these regions were directly amplified by PCR and sequenced to determine whether the HIF-1α mutation was specific to the tumor. Results. Although the HIF-1α cDNAs of all cell lines, the normal prostate, and three of the tumors were found to have a wildtype sequence, HIF-1α cDNAs amplified from two hormone-resistant tumors had nucleic acid substitutions that resulted in significant amino acid changes within the ODD domain of the HIF-1α protein. Analysis of the DNA extracted from a benign or tumorous region of one of these specimens showed that only the wildtype (nonmutated) form of the HIF-1α gene was amplified from the normal DNA whereas only the mutated form of the HIF-1α gene was amplified from the tumor. Conclusions. Some human hormone-refractory prostate cancers have mutations in a critical regulatory domain of the HIF-1α protein. We believe that these mutations might enable expression of this protein under inappropriate conditions and contribute to the development of therapeutic resistance by the cancer cells. This hypothesis is currently being tested.

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