From AR to c-Met: Androgen deprivation leads to a signaling pathway switch in prostate cancer cells

Liu, Tiancheng; Mendes, Desiree E.; Berkman, Clifford E.

doi:10.3892/ijo.2013.2020

Cited by 21 publications

(31 citation statements)

References 25 publications

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“…1) clearly demonstrated that overexpression of calpain 2 was observed in long-term androgen-deprived LNCaP cells (10, 20 passages) and PC-3 cells (AR-negative), of which, AR was confirmed to be no longer detectable in our previous work (10,25). In contrast, calpain 1 expression was relatively stable in both AR-positive and AR-negative prostate cancer cells.…”

Section: Resultsmentioning

confidence: 53%

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Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Liu

Mendes

Berkman

2013

International Journal of Oncology

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Understanding the molecular mechanism of prostate cancer progression from androgen dependence to independence may lead to developing more effective treatments against prostate cancer. Herein, our previous in vitro model was employed to assess the effects of continuous androgen-deprivation on developing the metastatic phenotype from androgen-dependent prostate cancer cells (LNCaP). The results indicated that long-term androgen deprivation resulted in overexpression of calpain 2 and increased expression of filamin A (FlnA), but not for calpain 1. The enhanced activity of calpain 2 was confirmed by the accumulation of cleaved FlnA fragments, which could be effectively blocked by calpeptin (an inhibitor of calpain 2). Therefore, the combination of calpain 2 inhibitor and androgen deprivation may provide new therapeutic strategy for patients to prevent or postpone prostate cancer progression.

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Section: Resultsmentioning

confidence: 53%

“…2) in long-term androgen-deprived LNCaP cells (10, 20 passages) and AR-negative PC-3 cells (10,25). The increase of cleaved FlnA fragments (Fig.…”

Section: Resultsmentioning

confidence: 99%

Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Liu

Mendes

Berkman

2013

International Journal of Oncology

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“…Normally, the expression of c-met is downregulated by the AR [64]. However, during long-time ADT an overexpression of c-met was observed, which is associated with a more aggressive disease [65]. Cabozantinib, an inhibitor of c-met and VEGFR2, was shown to improve metastatic lesions and to increase progression free survival of patients with CRPC [66].…”

Section: Growth Factor Signalingmentioning

confidence: 97%

Androgen deprivation of prostate cancer: Leading to a therapeutic dead end

2015

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Androgen deprivation therapy (ADT) is considered as the standard therapy for men with de novo or recurrent metastatic prostate cancer. ADT commonly leads to initial biochemical and clinical responses. However, several months after the beginning of treatment, tumors become castration-resistant and virtually all patients show disease progression. At this stage, tumors are no longer curable and cancer treatment options are only palliative. In this review, we describe molecular alterations in tumor cells during ADT, which lead to deregulation of different signaling pathways and castration-resistance, and how they might interfere with the clinical outcome of different second-line therapeutics. A recent breakthrough finding that early chemotherapy is associated with a significant survival benefit in metastatic hormone-sensitive disease highlights the fact that there is time for a fundamental paradigm shift in the treatment of advanced prostate cancer. Therapeutic intervention seems to be indicated before a castration-resistant stage is reached to improve therapeutic outcome and to reduce undesirable side effects.

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“…Verras et al showed that AR represses c-Met expression directly through binding in its promoter while castration was found to induce c-Met expression in LNCaP xenografts [91]. Interestingly, long term androgen deprivation leads to a signaling pathway switch from AR to c-Met which could be predictive of a more aggressive disease [92], while cabozatinib, a c-Met inhibitor leads to increased progression-free survival, improvement of bone scans and reduction of soft tissue lesions patients with mCRPC [93]. However, two phase III clinical trials evaluating the efficacy Cabozatinib in combination with prednisonde and mitoxantrone for patients with mCRPC failed to reach their primary endpoint of improved survival compared to prednisone and mitoxantrone alone (COMET-1, NCT01605227 and COMET-2, NCT01522443).…”

Section: Introductionmentioning

confidence: 99%

Understanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level

et al. 2015

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Context To evaluate molecular mechanisms that play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer. Objective The understanding of mechanisms and biological pathways associated with the progression of prostate cancer under systemic androgen depletion or administration of novel anti-androgens abiraterone, enzalutamide and ARN-509. This review also examines the introduction of novel combinational approaches for patients with castrate resistant prostate cancer. Evidence Acquisition Pubmed was the data source and “castrate resistant prostate cancer”, “abiraterone, enzalutamide resistance mechanisms”, “resistance to androgen deprivation”, “AR mutations”, “amplifications”, “splice variants” and “AR alterations” were the keywords for the search. Papers published before 1990 were excluded from the review and only English papers were included. Evidence Synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of castrate resistant prostate cancer and the acquisition of resistance to novel anti-androgen axis agents. It focuses on androgen biosynthesis in the tumor microenvironment, AR alterations and post-transcriptional modifications, the role of glucocorticoid receptor, pathways of cellular stress and alternative oncogenic signaling which are de-repressed upon maximum AR inhibition promoting cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in prostate cancer are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses . Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with castrate resistant prostate cancer. Patient Summary In this review we looked for mechanisms related to the progression of prostate cancer in patients undergoing hormonal therapy and treatment with novel drugs targeting the androgen receptor. Based on recent data, the combination of maximal androgen receptor inhibition with novel agents targeting other tumor compensatory, non-AR related pathways may improve the survival and quality of life of patients with castrate-resistant prostate cancer (CRPC).

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From AR to c-Met: Androgen deprivation leads to a signaling pathway switch in prostate cancer cells

Cited by 21 publications

References 25 publications

Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Androgen deprivation of prostate cancer: Leading to a therapeutic dead end

Understanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level

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