scholarly journals Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1991 ◽  
Author(s):  
Carmen A. Banuelos ◽  
Yusuke Ito ◽  
Jon K. Obst ◽  
Nasrin R. Mawji ◽  
Jun Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Androgen Receptor ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Splice Variants ◽  
Inhibitory Effect ◽  
Full Length ◽  
Brdu Incorporation ◽  
Prostate Cancer Cells

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

Inhibitory effect of acetyl-11-keto-β-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells

2008 ◽  
Vol 75 (11) ◽  
pp. 2112-2121 ◽  
Author(s):  
Hui-Qing Yuan ◽  
Feng Kong ◽  
Xiao-Ling Wang ◽  
Charles Y.F. Young ◽  
Xiao-Yan Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Boswellic Acid ◽  
Prostate Cancer Cells

scholarly journals Novel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells

2011 ◽  
Vol 286 (41) ◽  
pp. 36152-36160 ◽  
Author(s):  
Xi Yang ◽  
Zhiyong Guo ◽  
Feng Sun ◽  
Wei Li ◽  
Alan Alfano ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Membrane ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Splice Variant ◽  
Splice Variants ◽  
Response To Treatment ◽  
Castration Resistance ◽  
Prostate Cancer Cells ◽  
Castration Resistant

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors.

scholarly journals Zerumbone Regulates DNA Repair Responding to Ionizing Radiation and Enhances Radiosensitivity of Human Prostatic Cancer Cells

2017 ◽  
Vol 17 (2) ◽  
pp. 292-298 ◽  
Author(s):  
Pai-Kai Chiang ◽  
Wei-Kung Tsai ◽  
Marcelo Chen ◽  
Wun-Rong Lin ◽  
Yung-Chiong Chow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Prostatic Cancer ◽  
Radiation Sensitivity ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Damage Repair ◽  
Radiation Induced

Introduction. Radiation therapy using ionizing radiation is widely used for the treatment of prostate cancer. The intrinsic radiation sensitivity of cancer cells could be enhanced by modulating multiple factors including the capacity to repair DNA damage, especially double-strand breaks (DSBs). We aimed to examine the effect of zerumbone on radiation sensitivity and its protective effects against ionizing radiation–induced DSB in human prostate cancer cells. Materials and Methods. The human prostate cancer PC3 and DU145 cell lines were used. A colony formation assay was performed to analyze the radiation survival of cells. DNA histogram and generation of reactive oxygen species (ROS) were examined using flow cytometry. Western blotting was used to examine the expression of regulatory molecules related to DNA damage repair. Results. Pretreatment with zerumbone enhanced the radiation effect on prostate cancer cells. Zerumbone delayed the abrogation of radiation-induced expression of γ-H2AX, an indicator of DNA DSB. Zerumbone pretreatment markedly reduced ionizing radiation–induced upregulated expression of phosphorylated ATM (ataxia telangiectasia-mutated), which was partially reversed by the ATM agonist methyl methanesulfonate. Ionizing radiation augmented and zerumbone pretreatment reduced the expression of Jak2 and Stat3, which are involved in DNA damage repair signaling. No significant effect on the generation of ROS and expression of ATR was noted after zerumbone treatment. Conclusion: Zerumbone sensitized DU145 and PC3 prostatic cancer cells to ionizing radiation by modulating radiation-induced ATM activation during repair of DNA DSBs.

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