Abstract:The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients… Show more
“…RWPE1, LNCaP, PC3, C4-2B, DU145, CWR22V1, and HEK293 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA). C4-2B cells resistant to enzalutamide (C4-2B-MDVR) were generated by culturing C4-2B cells to increasing concentrations of enzalutamide (5–40 µM) in media for over 12 months and maintained in complete media supplemented with 20 µM enzalutamide as described previously [58, 59]. HEK293 cells were cultured in complete DMEM medium.…”
During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance. Previously, we showed that KDM8 is involved in the regulation of cell cycle and tumor metabolism in breast cancer cells. Its role in prostate cancer has not been explored. Here, we show that KDM8's oncogenic properties in prostate cancer come from its direct interaction (1) with AR to affect androgen response and (2) with PKM2 to regulate tumor metabolism. The interaction with AR leads to the elevated expression of androgen response genes in androgen-deprived conditions. They include ANCCA/ATAD2 and EZH2, which are directly targeted by KDM8 and involved in sustaining the survival of the cells under hormone-deprived conditions. Notably, in enzalutamide-resistant cells, the expressions of both KDM8 and EZH2 are further elevated, so are neuroendocrine markers. Consequently, EZH2 inhibitors or KDM8 knockdown both resensitize the cells toward enzalutamide. In the cytosol, KDM8 associates with PKM2, the gatekeeper of pyruvate flux and translocates PKM2 into the nucleus, where the KDM8/PKM2 complex serves as a coactivator of HIF-1α to upregulate glycolytic genes. Using shRNA knockdown, we validate KDM8's functions as a regulator for both androgen-responsive and metabolic genes. KDM8 thus presents itself as an ideal therapeutic target for metabolic adaptation and castration-resistance of prostate cancer cells.
“…RWPE1, LNCaP, PC3, C4-2B, DU145, CWR22V1, and HEK293 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA). C4-2B cells resistant to enzalutamide (C4-2B-MDVR) were generated by culturing C4-2B cells to increasing concentrations of enzalutamide (5–40 µM) in media for over 12 months and maintained in complete media supplemented with 20 µM enzalutamide as described previously [58, 59]. HEK293 cells were cultured in complete DMEM medium.…”
During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance. Previously, we showed that KDM8 is involved in the regulation of cell cycle and tumor metabolism in breast cancer cells. Its role in prostate cancer has not been explored. Here, we show that KDM8's oncogenic properties in prostate cancer come from its direct interaction (1) with AR to affect androgen response and (2) with PKM2 to regulate tumor metabolism. The interaction with AR leads to the elevated expression of androgen response genes in androgen-deprived conditions. They include ANCCA/ATAD2 and EZH2, which are directly targeted by KDM8 and involved in sustaining the survival of the cells under hormone-deprived conditions. Notably, in enzalutamide-resistant cells, the expressions of both KDM8 and EZH2 are further elevated, so are neuroendocrine markers. Consequently, EZH2 inhibitors or KDM8 knockdown both resensitize the cells toward enzalutamide. In the cytosol, KDM8 associates with PKM2, the gatekeeper of pyruvate flux and translocates PKM2 into the nucleus, where the KDM8/PKM2 complex serves as a coactivator of HIF-1α to upregulate glycolytic genes. Using shRNA knockdown, we validate KDM8's functions as a regulator for both androgen-responsive and metabolic genes. KDM8 thus presents itself as an ideal therapeutic target for metabolic adaptation and castration-resistance of prostate cancer cells.
“…Structure-based virtual screening is another effective way to obtain the lead compound of antiandrogens. For example, combining virtual screening and further biological assay, a lead compound, VPC-3033 (Figure 5 ), was identified to demonstrated strong androgen displacement potency which effectively inhibited AR transcriptional activity possess, profoundly degraded AR and significantly suppressed enzalutamide resistance PCa cells (Li et al, 2013a ). Moreover, through structure-based virtual screening using the FlexX docking model, 54 candidates were selected and further screened for AR antagonism via cell-based tests.…”
Section: Rational Antiandrogen Design To Circumvent Drug Resistance Dmentioning
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current clinically used antiandrogens such as flutamide, bicalutamide, and newly approved enzalutamide mainly target the hormone binding pocket (HBP) of AR. However, over time, drug resistance invariably develops and switches these antiandrogens from antagonist to agonist of the AR. Accumulated evidence indicates that AR mutation is an important cause for the drug resistance. This review will give an overview of the mutation based resistance of the current clinically used antiandrogens and the rational drug design to overcome the resistance, provides a promising strategy for the development of the new generation of antiandrogens targeting HBP.
“…Rosuvastatin precursor 1aq 68 could be oxidized to the corresponding aldehyde in 76% yield within only 10 min, which presented the potential application prospect of this protocol. Fluorenol ( 1bk ) 69 was oxidized to the corresponding ketones in good yields (86%).Fig. 6Electrochemical oxidation of biologically relevant substrates.…”
Alcohol oxidation reactions are widely used for the preparation of aldehydes and ketones. The electrolysis of alcohols to carbonyl compounds have been underutilized owing to low efficiency. Herein, we report an electrochemical oxidation of various alcohols in a continuous-flow reactor without external oxidants, base or mediators. The robust electrochemical oxidation is performed for a variety of alcohols with good functional group tolerance, high efficiency and atom economy, whereas mechanistic studies support the benzylic radical intermediate formation and hydrogen evolution. The electrochemical oxidation proves viable on diols with excellent levels of selectivity for the benzylic position.
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