The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive statein vitro, and YAP conferred castration resistancein vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase–ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC).

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PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0303 ◽

2014 ◽

Vol 53 (1) ◽

pp. 31-41 ◽

Cited By ~ 9

Author(s):

Momoe Itsumi ◽

Masaki Shiota ◽

Akira Yokomizo ◽

Ario Takeuchi ◽

Eiji Kashiwagi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Therapeutic Effects ◽

Castration Resistant Prostate Cancer ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Cellular Apoptosis ◽

Resistant Cells

Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti-androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA-resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro-proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castration-resistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.

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Aspalathin-rich green Aspalathus linearis extract suppresses migration and invasion of human castration-resistant prostate cancer cells via inhibition of YAP signaling

Phytomedicine ◽

10.1016/j.phymed.2020.153210 ◽

2020 ◽

Vol 69 ◽

pp. 153210

Author(s):

Shih-Han Huang ◽

Yung-Hsi Kao ◽

Christo J.F. Muller ◽

Elizabeth Joubert ◽

Chih-Pin Chuu

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Migration And Invasion ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Aspalathus Linearis

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Castration-resistant Prostate Cancer: The Targeting of Bone Microenvironment-related Survival Factors For Prostate Cancer Cells

Clinical Cancer Drugs ◽

10.2174/2212697x03666151203202934 ◽

2016 ◽

Vol 3 (1) ◽

pp. 16-22 ◽

Cited By ~ 1

Author(s):

Dimitrios Karamanolakis ◽

Athanasios Armakolas ◽

Michael Koutsilieris

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Bone Microenvironment ◽

Prostate Cancer Cells ◽

Survival Factors ◽

Castration Resistant ◽

Related Survival

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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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