Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

Khurana, Namrata; Sikka, Suresh C.

doi:10.3390/ijms20092066

Cited by 53 publications

(50 citation statements)

References 124 publications

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“…SOX9 drives prostate cancer development through various mechanisms, particularly related to WNT/β-catenin signaling activation [304]. β-catenin forms a complex with AR and through this mechanism augments AR signaling in prostate cancer [574].…”

Section: Prostate Cancer Stem Cellsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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Section: Prostate Cancer Stem Cellsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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“…APC gene mutations were first reported in FAP in 1991, and the progression from adenoma to cancer is thought to involve multistage carcinogenesis with accumulation of APC , KRAS and TP53 gene mutations [ 3 , 4 ]. WNT is a secreted glycoprotein that mediates cell proliferation, differentiation, motility, and polarity during embryonic and organ development [ 5 ]. β-catenin is a key effector in the Wnt signaling pathway, which controls cytoskeleton activity and cell movement via both β-catenin-dependent and -independent pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling was shown to be involved in the progression of prostatic intraepithelial neoplasia (PIN) to prostate adenocarcinoma in mouse prostate cancer models and to induce high-grade PIN in differentiated luminal cells [ 5 ]. Abnormal immunoexpression of β-catenin in prostate cancer cells was found to increase the risk of death from tumor progression, and changes in immunohistochemical staining of β-catenin associated with high Gleason scores may have prognostic value.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal immunoexpression of β-catenin in prostate cancer cells was found to increase the risk of death from tumor progression, and changes in immunohistochemical staining of β-catenin associated with high Gleason scores may have prognostic value. β-catenin overexpression has been linked to prostate cancer progression, high-grade intraepithelial neoplasia, and resistance to castration in several genetically engineered mouse models [ 5 ]. Genetic analysis studies have found APC mutations in 4% of patients with locoregional prostate cancer, that APC alterations were enriched in metastatic (15%) versus locoregional disease, and that 24% of patients with ductal carcinoma of the prostate had APC mutations [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

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A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report

et al. 2020

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Background Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli ( APC ) gene mutation in Japan. Case presentation An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. Conclusion To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

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“…Prostate-specific antigen (PSA), secreted by prostatic epithelial cells, is a serum indicator used to diagnose the incidence of prostate cancer [30]. PSA testing is a sensitive way to detect the tumor growth rate in prostate cancer patients [63]. The levels of androgen and its receptor (androgen receptor, AR) play essential roles in the early development of prostate cancer [40,64,65,66].…”

Section: Cdk5 and Prostate Cancermentioning

confidence: 99%

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

Oner

Lin

Chen

et al. 2019

IJMS

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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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Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

Cited by 53 publications

References 124 publications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report

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

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