Enzalutamide Potentiates Radiation Response via Impairment of DNA Damage Repair Process in Prostate Cancer Cells

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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BTF3 confers oncogenic activity in prostate cancer through transcriptional upregulation of Replication Factor C

Cell Death and Disease ◽

10.1038/s41419-020-03348-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yuan Zhang ◽

Xiang Gao ◽

Jingyan Yi ◽

Xiaolin Sang ◽

Zhihong Dai ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Transcription Factor ◽

Cancer Cells ◽

Replication Factor C ◽

Prostate Cancer Cells ◽

Damage Repair ◽

Factor C ◽

Oncogenic Transcription Factor

AbstractHigh levels of Basic Transcription Factor 3 (BTF3) have been associated with prostate cancer. However, the mechanisms underlying the role of BTF3 as an oncogenic transcription factor in prostate tumorigenesis have not been explored. Herein, we report that BTF3 confers oncogenic activity in prostate cancer cells. Mechanistically, while both BTF3 splicing isoforms (BTF3a and BTF3b) promote cell growth, BTF3b, but not BTF3a, regulates the transcriptional expression of the genes encoding the subunits of Replication Factor C (RFC) family that is involved in DNA replication and damage repair processes. BTF3 knockdown results in decreased expression of RFC genes, and consequently attenuated DNA replication, deficient DNA damage repair, and increased G2/M arrest. Furthermore, knockdown of the RFC3 subunit diminishes the growth advantage and DNA damage repair capability conferred by ectopic overexpression of BTF3b. Importantly, we show that enforced BTF3 overexpression in prostate cancer cells induces substantial accumulation of cisplatin-DNA adducts and render the cells more sensitive to cisplatin treatment both in vitro and in vivo. These findings provide novel insights into the role of BTF3 as an oncogenic transcription factor in prostate cancer and suggest that BTF3 expression levels may serve as a potential biomarker to predict cisplatin treatment response.

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DNA damage repair gene mutation testing and genetic counseling in men with/without prostate cancer: a systematic review

Future Oncology ◽

10.2217/fon-2020-0569 ◽

2020 ◽

Author(s):

Nigel Armstrong ◽

Ruben GW Quek ◽

Steve Ryder ◽

Janine Ross ◽

Titas Buksnys ◽

...

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

At Risk ◽

Dna Damage ◽

Clinical Trials ◽

Genetic Counseling ◽

Mutation Screening ◽

Dna Damage Repair ◽

Mutation Testing ◽

Damage Repair

Background: Ongoing clinical trials are investigating poly(ADP-ribose) polymerase (PARP) inhibitors to target the DNA damage repair (DDR) pathway in prostate cancer. DDR mutation screening will guide treatment strategy and assess eligibility for clinical trials. Materials & methods: This systematic review estimated the rate of DDR mutation testing or genetic counseling among men with or at risk of prostate cancer. Results: From 6856 records, one study fulfilled the inclusion criteria and described men undiagnosed with prostate cancer with a family history of BRCA1/2 mutation who received DDR mutation testing. Conclusion: With only one study included in this first systematic review of DDR mutation testing or genetic counseling in men with or at risk of prostate cancer, more research is warranted.

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