The Role of DHEAS in Abiraterone Resistant Prostate Cancer
Technical Report,01 Jul 2018,30 Jun 2019
Cleveland Clinic Foundation Cleveland United States
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Prostate cancer PCa is a leading cause of cancer deaths in American men. Androgen deprivation therapy ADT, lowers to castrate levels the androgens that drive PCa growth through androgen receptor AR signaling. Despite initial success, castration-resistant PCa CRPC develops within 24 months of ADT and remains primarily driven by androgens. Abirateroneacetate, a CYP17A1 inhibitor, reduces circulating androgen levels by preventing the synthesis of dehydroepiandrosteroneDHEA and its sulfated form DHEAS, an androgen precursor. Although most patients respond well to abiraterone acetate, survival is prolonged by only about 4-5 months, and secondary resistance develops. Hypoxia is a hallmark of many types of human tumors and implicated in clinical behavior and treatment response. Preclinical study indicate that hypoxia promotes both local aggressiveness and metastasis via mediating metabolism of cancer cells to facilitate the rapid growth of tumor. Previous study suggest that hypoxia plays a critical role in prostate cancer development. Here I further determined how hypoxia affected DHEA metabolism via regulating the expression of HSD3B1 as well as co-factors required for HSD3B1activity. I established hypoxia-resistant cell lines which can survive under hypoxia forever to simulate the hypoxic condition that exists in a tumor. My results indicate that while acute hypoxia leads to deaccelerated conversion of DHEA to downstream metabolites due to reduced co-factors, long-term hypoxia significantly increases the expression of HSD3B1 at both mRNA and protein level. HSD3B1 exhibits higher stability under hypoxia. Moreover, my study suggest that hypoxia-resistant cells exhibit faster conversion of DHEA to downstream metabolites than hypoxia-sensitive cells after reoxygenation.
- Medicine and Medical Research