Overcoming CRPC Treatment Resistance via Novel Dual AKR1C3 Targeting
Technical Report,30 Sep 2016,29 Sep 2017
University of California, Davis Davis United States
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AKR1C3 is the major AKR1C isozyme expressed in the human prostate and elevated expression of this enzyme has been associated with prostate cancer progression and aggressiveness. Our hypothesis is that targeting AKR1C3 decreases intracrine androgens and AR variants and improves enzalutamide therapy against metastatic CRPC. During the first funding year, we demonstrated that AKR1C3 affected intracrine androgen biosynthesis. We introduced constructs expressing AKR1C3 under the control of doxycycline into LNCaP cells. We validated the biological function of the tet-inducible ARK1C3 in LNCaPTRAKR1C3 cells. When the gene was not induced, cell growth was readily inhibited by anti-androgens abiraterone ABI and enzalutamide Enza. With doxycycline induction, the control treatment would benefit from overexpression of AKR1C3 and partially overcome the ABI and Enza inhibition. We measured intracellular and intratumor androgen levels by LC-MS induced by AKR1C3 and found that AKR1C3 expression induces intracrine androgen synthesis. We also demonstrated that overexpression of AKR1C3 in orthotopic model of LNCaP-AKR1C3 tumor confers resistance to enzalutamide treatment. These studies support the roles of AKR1C3 in intracrine androgen synthesis and confers resistance to enzalutamide.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology