Role of the Bcl-2 Gene Family in Prostate Cancer Progression and Its Implications for Therapeutic Intervention

Chaudhary, Khurram; Abel, Paul; Lalani, El–Nasir

doi:10.2307/3434471

Cited by 18 publications

(30 citation statements)

References 33 publications

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“…Both in vitro and in vivo studies have established that Bcl-2 expression confers anti-apoptotic activity in prostate cancer and its overexpression is linked to progression into advanced prostate cancer. 50 Bcl-2 overexpression has also been correlated with high PSA levels in prostate cancer. 36 Hence, Bcl-2 protein levels were measured after urolithin incubation.…”

Section: Urolithins a And B Induce Apoptosis And A Decrease Of Bcl-2 mentioning

confidence: 99%

Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells

et al. 2014

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Walnuts have been gathering attention for their health-promoting properties. They are rich in polyphenols, mainly ellagitannins (ETs) that after consumption are hydrolyzed to release ellagic acid (EA). EA is further metabolized by microbiota to form urolithins, such as A and B, which are absorbed. ETs, EA and urolithins have shown to slow the proliferation and growth of different types of cancer cells but the mechanisms remain unclear. We investigate the role of urolithins in the regulatory mechanisms in prostate cancer, specifically those related to the androgen receptor (AR), which have been linked to the development of this type of cancer. In our study, urolithins down-regulated the mRNA and protein levels of both prostate specific antigen (PSA) and AR in LNCaP cells. The luciferase assay performed with a construct containing three androgen response elements (AREs) showed that urolithins inhibit AR-mediated PSA expression at the transcriptional level. Electrophoretic mobility shift assays revealed that urolithins decreased AR binding to its consensus response element. Additionally, urolithins induced apoptosis in LNCaP cells, and this effect correlated with a decrease in Bcl-2 protein levels. In summary, urolithins attenuate the function of the AR by repressing its expression, causing a down-regulation of PSA levels and inducing apoptosis. Our results suggest that a diet rich in ET-containing foods, such as walnuts, could contribute to the prevention of prostate cancer.

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Section: Urolithins a And B Induce Apoptosis And A Decrease Of Bcl-2 mentioning

confidence: 99%

Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells

et al. 2014

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“…35 Bcl-2 contributes not only to development of cancer but also to chemoresistance. 43 Hsp27 has been reported to be elevated in many human tumors and is a predictor of poor clinical outcome (androgen-independence), as it has a cytoprotective role by interfering with many key regulators of apoptosis. 37,44 Multiple RTKs, Bcl-2 and Hsp27 have all been implicated in hormone resistance, 41,45,46 and we have shown that Reg IV modulates the spectrum, therefore suggesting that a Reg IVtargeted therapy could have utility in drug resistant patient populations.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Vanderlaag¹,

Wang²,

Fayadat‐Dilman³

et al. 2011

Intl Journal of Cancer

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Regenerating islet‐derived family member, 4 (Reg IV) is a secreted protein and member of the C‐type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin‐like growth factor receptor as well as their downstream effectors, mitogen‐activated protein kinase and phosphatidylinositol‐3‐kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage‐dependent and anchorage‐independent (both soft‐agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl‐2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl‐2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA‐mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl‐2 and multiple RTKs.

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“…Hormonally refractive prostate cancers also show resistance to adjuvant treatment modalities, such as radioor chemotherapy, either alone or in combination (Chaudhary et al, 1999;Gopalkrishnan et al, 2001;Mabjeesh et al, 2002;Cooperberg et al, 2004). A potential reason for this inherent resistance involves elevated expression of members of the bcl-2 family that delimit apoptosis induction by chemotherapy and ionizing radiation (IR), namely bcl-x L and bcl-2 (Reed et al, 1996;Chaudhary et al, 1999;Catz and Johnson, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…A potential reason for this inherent resistance involves elevated expression of members of the bcl-2 family that delimit apoptosis induction by chemotherapy and ionizing radiation (IR), namely bcl-x L and bcl-2 (Reed et al, 1996;Chaudhary et al, 1999;Catz and Johnson, 2003). Accordingly, numerous studies support a relationship between bcl-x L and bcl-2 expression and prostate cancer development and progression (Colombel et al, 1993;Krajewski et al, 1994Bauer et al, 1996;Reed et al, 1996;Liu and Stein, 1997;Keshgegian et al, 1998;Bai et al, 1999;Chaudhary et al, 1999;Lebedeva et al, 2000;Li et al, 2001;Catz and Johnson, 2003). Expression of both Bcl-x L (100%) and Bcl-2 (25%) proteins occur frequently in prostate carcinomas (Colombel et al, 1993;Krajewski et al, 1994, Bcl-2 staining increases with Gleason grade and represents an indicator of poor prognosis in prostate cancer (Colombel et al, 1993;Bauer et al, 1996;Krajewska et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2

Lebedeva

Sarkar

et al. 2005

Oncogene

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Role of the Bcl-2 Gene Family in Prostate Cancer Progression and Its Implications for Therapeutic Intervention

Cited by 18 publications

References 33 publications

Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells

Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2

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