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P53-dependent CD51 expression contributes to characteristics of cancer stem cells in prostate cancer.

ABSTRACT: Castration-resistant prostate cancer (CRPC), which is considered to contain cancer stem cells (CSCs), leads to a high relapse rate in patients with prostate cancer (PCa). However, the markers of prostate CSCs are controversial. Here we demonstrate that CD51, in part, correlates with the poor prognosis of PCa patients. Further, we find that CD51 is a functional molecule that is able to promote the malignancy of PCa through enhancing tumor initiation, metastatic potential, and chemoresistance. Moreover, we find that elevated CD51 expression in PCa specimens correlates with p53 loss of function. Mechanistically, we demonstrate that p53 acts via Sp1/3 to repress CD51 transcription, and CD51 is required for PCa stemness and metastasis properties, and is downregulated by p53. Taken together, these results indicate that CD51 is a novel functional marker for PCa, which may provide a therapeutic target for the efficiently restricting PCa progression.

SUBMITTER: Sui X

PROVIDER: S-EPMC5943274 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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p53-dependent CD51 expression contributes to characteristics of cancer stem cells in prostate cancer.

Sui Xin X Cai Jianye J Li Hongyu H He Chenchen C Zhou Congya C Dong Yiping Y Chen Li L Zhang Bin B Wang Yingnan Y Zhang Yanan Y Qiu Yuan Y Zhang Yuanyuan Y Zhao Yang Y Huang Yinong Y Shen Yutian Y Wu Haoxiang H Xiao Jiaqi J Mason Clifford C Zhu Qing Q Han Suxia S

Cell death & disease 20180501 5

Castration-resistant prostate cancer (CRPC), which is considered to contain cancer stem cells (CSCs), leads to a high relapse rate in patients with prostate cancer (PCa). However, the markers of prostate CSCs are controversial. Here we demonstrate that CD51, in part, correlates with the poor prognosis of PCa patients. Further, we find that CD51 is a functional molecule that is able to promote the malignancy of PCa through enhancing tumor initiation, metastatic potential, and chemoresistance. Mor ...[more]

PMID: 29743605

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Project description:PurposeIncreased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer.Experimental designThe effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status.ResultsMDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and ?-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment.ConclusionMDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer.Translational relevanceThe combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.

Dataset Information

P53-dependent CD51 expression contributes to characteristics of cancer stem cells in prostate cancer.

Publications

p53-dependent CD51 expression contributes to characteristics of cancer stem cells in prostate cancer.

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