Myc confers androgen-independent prostate cancer cell growth

Bernard, David; Pourtier-Manzanedo, Albin; Gil, Jesús; Beach, David

doi:10.1172/jci19035

Cited by 123 publications

(143 citation statements)

References 36 publications

(52 reference statements)

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“…Isosilybin B ranked the most potent flavonolignan for nearly all end points including inhibition of prostate-specific antigen (PSA) secretion (Davis-Searles et al, 2005), which is used as a clinical tool in screening, diagnosis and treatment decisions for human PCA (Nelson et al, 2003). Here we conducted detailed mechanistic studies with isosilybin B focusing on AR by employing androgen-dependent LNCaP cells with single AR mutation (T877A), LAPC4 cells with wild-type AR and androgen-independent 22Rv1 cells with mutated AR (H874Y), though all the three cell lines have functional AR (Nagabhushan et al, 1996;Klein et al, 1997;Mendoza et al, 2002;Bernard et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

et al. 2008

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The identification and development of novel nontoxic phytochemicals that target androgen and androgen receptor (AR) signaling remains a priority for prostate cancer (PCA) control. In the present study, we assessed the antiandrogenic efficacy of isosilybin B employing human PCA LNCaP (mutated AR), 22Rv1 (mutated AR) and LAPC4 (wild-type AR) cells. Isosilybin B (10-90 lM) treatment decreased the AR and prostate specific antigen (PSA) levels in LNCaP, 22Rv1 and LAPC4 cells, but not in non-neoplastic human prostate epithelial PWR-1E cells. Isosilybin B treatment also inhibited synthetic androgen R1881-induced nuclear localization of AR, PSA expression and cell growth, and caused G 1 arrest. In mechanistic studies identifying AR degradation, isosilybin B caused increased phosphorylation of Akt (Ser-473 and Thr-308) and Mdm2 (Ser-166), which was linked with AR degradation as pretreatment with PI3K inhibitor (LY294002)-restored AR level. Further, overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation. Antibody pull-down results also indicated that isosilybin B treatment enhances the formation of complex between Akt, Mdm2 and AR, which promotes phosphorylation-dependent AR ubiquitination and its degradation by proteasome. Together, present findings identify a novel mechanism for isosilybin B-mediated anticancer effects in human PCA cells.

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Section: Introductionmentioning

confidence: 99%

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

et al. 2008

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“…Accordingly, other c-Myc activities, such as induction of cell proliferation, are also blocked by dominant-negative ezrin variants, although overexpression of ezrin alone does not significantly enhance androgen-induced cell proliferation. This indicates that c-Myc also have ezrin-independent tumor-promoting actions (Bernard et al, 2003), some of which could contribute to the invasion-promoting activity of c-Myc.…”

Section: Discussionmentioning

confidence: 96%

“…We also analyzed a set of PCa (n ¼ 10) and benign prostatic hyperplasia (n ¼ 4) samples for co-expression of c-Myc and ezrin by immunofluorescence and confirmed that in all samples analyzed there is a significant overlap between c-Myc and ezrin expression levels in epithelial cells (Supplementary Figure 1). Although c-Myc overexpression stimulated cell proliferation in an androgenindependent manner (Supplementary Figure 2A; Bernard et al, 2003), little cell invasion is observed in the absence of androgen stimulation in cells overexpressing c-Myc (Figure 1c). Conversely, cells overexpressing c-Myc protein show a significantly increased invasive capacity on androgen treatment.…”

Section: C-myc Regulates Pca Cells Invasion In Vitromentioning

confidence: 99%

“…Figure 2 Increased expression of c-Myc induces the proliferation and increases the tumorigenicity of LNCaP-FGC cells (Bernard et al, 2003). Therefore, we measured the proliferation and tumorigenic potential of cells overexpressing c-Myc as well as different ezrin variants in the presence of androgen.…”

Section: Ezrin Mediates the Activity Of C-myc In Pca Cellsmentioning

confidence: 99%

“…This assay was carried out as previously described (Bernard et al, 2003). Each plate was seeded with 1 Â 10 5 cells.…”

Section: Western Blottingmentioning

confidence: 99%

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Ezrin mediates c-Myc actions in prostate cancer cell invasion

Iglesias-Gato

Fernández-Pérez

et al. 2009

Oncogene

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The forced overexpression of c-Myc in mouse prostate and in normal human prostate epithelial cells results in tumor transformation with an invasive phenotype. How c-Myc regulates cell invasion is poorly understood. In this study, we have investigated the interplay of c-Myc and androgens in the regulation of prostate cancer cell invasion. We found that c-Myc induces cell invasion and anchorageindependent growth by regulating ezrin protein expression in the presence of androgens. The activity of the ezrin promoter is controlled by androgens through c-Myc, which binds to a phylogenetically conserved E-Box located in the proximal promoter region. Besides, we also show that ezrin is an important regulator of c-Myc protein levels. These effects are achieved through androgeninduced changes in ezrin phosphorylation, which results in the regulation of downstream signals. These downstream signals involve the modulation of Akt and GSK-3b activity resulting in increased c-Myc protein synthesis and inhibition of its degradation. In summary, we have shown a key role for ezrin as a mediator of c-Myc-induced tumorigenesis in prostate cancer cells.

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Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

Islam

Zhou

Chen

et al. 2019

Cell Biochemistry & Function

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Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs.

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Myc confers androgen-independent prostate cancer cell growth

Cited by 123 publications

References 36 publications

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

Ezrin mediates c-Myc actions in prostate cancer cell invasion

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

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