Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications

Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5–p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future.

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How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation?

British Journal Of Nutrition ◽

10.1017/s0007114511005770 ◽

2011 ◽

Vol 108 (3) ◽

pp. 424-430 ◽

Cited By ~ 4

Author(s):

Mu Yao ◽

Chanlu Xie ◽

Maryrose Constantine ◽

Sheng Hua ◽

Brett D. Hambly ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

East Asia ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Prostate Cancer Cell ◽

Cancer Cell Proliferation ◽

Prostate Cancer Cells ◽

The Mediterranean

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8 %) for 72 h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2′-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

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FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01891-08 ◽

2010 ◽

Vol 30 (5) ◽

pp. 1243-1253 ◽

Cited By ~ 92

Author(s):

Li Ni ◽

Chun-Song Yang ◽

Daniel Gioeli ◽

Henry Frierson ◽

David O. Toft ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Feedback Loop ◽

Critical Role ◽

Prostate Cancer Cells ◽

Androgen Receptor Signaling ◽

Hsp90 Chaperone ◽

Chaperone Complex ◽

Androgen Binding

ABSTRACT Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.

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Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

BioMed Research International ◽

10.1155/2020/2406159 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Yuanshen Mao ◽

Wenfeng Li ◽

Bao Hua ◽

Xin Gu ◽

Weixin Pan ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Progression ◽

Prostate Cancer Cells ◽

Migration Inhibition ◽

Akt Inhibitor ◽

Phase Arrest ◽

M Phase ◽

And Migration

ELK3, an ETS domain-containing transcription factor, participates in various physiological and pathological processes including cell proliferation, migration, angiogenesis, and malignant progression. However, the role of ELK3 in prostate cancer cells and its mechanism are not fully understood. The contribution of ELK3 to prostate cancer progression was investigated in the present study. We showed that silencing of ELK3 by siRNA in prostate cancer cell DU145 induced S-M phase arrest, promoted apoptosis, inhibited cell proliferation and migration in vitro, and suppressed xenograft growth in mice in vivo. In accordance with its ability to arrest cells in S-M phase, the expression of cyclin A and cyclin B was downregulated. In addition, the expression of p53 was upregulated following ELK3 knockdown, while that of antiapoptotic Bcl-2 was decreased. The migration inhibition may partly due to upregulation of SERPINE1 (a serine protease inhibitor) followed ELK3 knockdown. Consistently, downregulation of SERPINE1 resulted in a modest elimination of migration inhibition resulted from ELK3 knockdown. Furthermore, we found that the AKT signaling was activated in ELK3 knockdown cells, and treatment these cells with AKT inhibitor attenuated SERPINE1 expression induced by ELK3 silencing, suggesting that activation of AKT pathway may be one of the reasons for upregulation of SERPINE1 after ELK3 knockdown. In conclusion, modulation of ELK3 expression may control the progression of prostate cancer partly by regulating cell growth, apoptosis, and migration.

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Material properties of disulfide-crosslinked hyaluronic acid hydrogels influence prostate cancer cell growth and metabolism

Journal of Materials Chemistry B ◽

10.1039/d0tb01570a ◽

2020 ◽

Vol 8 (42) ◽

pp. 9718-9733

Author(s):

Nicky W. Tam ◽

Dudley Chung ◽

Samuel J. Baldwin ◽

Jeffrey R. Simmons ◽

Lingling Xu ◽

...

Keyword(s):

Prostate Cancer ◽

Hyaluronic Acid ◽

Cell Growth ◽

Cancer Cells ◽

Material Properties ◽

Prostate Cancer Cell ◽

Prostate Cancer Cells ◽

Cancer Cell Growth ◽

Diffusion Limited ◽

Metastatic Cells

Studying prostate cancer cells embedded in hyaluronic acid hydrogels provides insight on how metastatic cells might behave in diffusion-limited tissue microenvironments.

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Inhibition of Recombining Binding Protein Suppressor of Hairless (RBPJ) Impairs the Growth of Prostate Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000430166 ◽

2015 ◽

Vol 36 (5) ◽

pp. 1982-1990 ◽

Cited By ~ 7

Author(s):

Li Xue ◽

Hecheng Li ◽

Qi Chen ◽

Zhenlong Wang ◽

Peng Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Growth ◽

Cancer Cells ◽

Receptor Activation ◽

Notch Signaling Pathway ◽

Notch Receptor ◽

Prostate Cancer Cells ◽

Cancer Cell Growth ◽

Promising Therapeutic Approach

Background/Aims: Notch signaling pathway regulates cancer cell growth. RBPJ is a key transcription factor downstream of Notch receptor activation, whereas the role of RBPJ in carcinogenesis of prostate cancer is ill-defined. Methods: Here, we evaluated the effects of RBPJ inhibition on the growth of prostate cancer cells. We knocked down RBPJ in prostate cancer cells by a short hairpin interfering RNA (shRNA). We measured cell growth by an MTT assay. We analyzed the levels of cell-cycle-associated proteins by Western blot. Results: We found that shRNA for RBPJ efficiently inhibited RBPJ expression in prostate cancer cells, resulting in a significant decrease in the cell growth. Further, RBPJ-mediated cell-growth inhibition appeared to be resulting from alteration of cell-cycle inhibitors p21 and p27, cell-cycle activators CDK2, CDK4 and CyclinD1, and apoptosis-suppressor Bcl-2. Conclusion: Our data suggest that shRNA intervention of RBPJ expression could be a promising therapeutic approach for treating human prostate cancer.

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