Impaired homologous recombination DNA repair and enhanced sensitivity to DNA damage in prostate cancer cells exposed to anchorage-independence

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

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Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous Recombination

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-18-1335 ◽

2019 ◽

Vol 17 (10) ◽

pp. 1985-1998 ◽

Cited By ~ 5

Author(s):

Satoshi Washino ◽

Leah C. Rider ◽

Lina Romero ◽

Lauren K. Jillson ◽

Trisiani Affandi ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Cancer Cells ◽

Prostate Cancer Cells

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IMPAIRMENT OF THE DNA REPAIR AND GROWTH ARREST PATHWAYS BY p53R2 SILENCING ENHANCES DNA DAMAGE- INDUCED APOPTOSIS IN A p53-DEPENDENT MANNER IN PROSTATE CANCER CELLS

The Journal of Urology ◽

10.1016/s0022-5347(08)61243-4 ◽

2008 ◽

Vol 179 (4S) ◽

pp. 424-424

Author(s):

Hong-lin Devlin ◽

Philip C Mack ◽

Rebekah A Burich ◽

Paul H Gumerlock ◽

Hsing-Jien Kung ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Growth Arrest ◽

Dependent Manner ◽

Prostate Cancer Cells ◽

Induced Apoptosis

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Impairment of the DNA Repair and Growth Arrest Pathways by p53R2 Silencing Enhances DNA Damage–Induced Apoptosis in a p53-Dependent Manner in Prostate Cancer Cells

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-07-2027 ◽

2008 ◽

Vol 6 (5) ◽

pp. 808-818 ◽

Cited By ~ 33

Author(s):

Hong-Lin Devlin ◽

Phillip C. Mack ◽

Rebekah A. Burich ◽

Paul H. Gumerlock ◽

Hsing-Jien Kung ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Growth Arrest ◽

Dependent Manner ◽

Prostate Cancer Cells ◽

Induced Apoptosis

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Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03369-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ding-fang Zhang ◽

Zhi-chun Yang ◽

Jian-qiang Chen ◽

Xiang-xiang Jin ◽

Yin-da Qiu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Dna Damage ◽

Cell Adhesion ◽

Anticancer Activity ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Dna Damage And Repair ◽

Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

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