Increased bcl-2 expression is associated with primary resistance to chemotherapy in human epithelial ovarian cancer

Kassim, Samar K.; Ali, H.A.M.; Sallam, Maha; Fayed, Salah T.; Seada, Laila; abd-Elkawy, Emtyaz; Seada, Maged Abu; Khalifa, Ali

doi:10.1016/s0009-9120(99)00026-0

Cited by 38 publications

(28 citation statements)

References 17 publications

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“…The Bcl-2 protein exerts an antiapoptotic function: it inhibits the release of cytochrome c into the cytosol which, in turn, activates caspase-9 and caspase-3, leading to apoptosis (18). The Bcl-2 gene has been found to be overexpressed in different cancers, including B-cell lymphoma (19), melanoma (20), neuroblastoma (21), breast (22), prostate (23), ovarian (24), and lung carcinomas (25). Bcl-2 and its homologues might intervene in oncogenesis at different levels by favoring the persistence of malignant cells that, in normal circumstances, would be eliminated by apoptosis, and also by promoting resistance to conventional cancer treatments (26).…”

Section: Introductionmentioning

confidence: 99%

High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of Bcl-2 Gene

et al. 2010

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We have previously described a mechanism through which the high-mobility group A1 (HMGA1) proteins inhibit p53-mediated apoptosis by delocalizing the p53 proapoptotic activator homeodomain-interacting protein kinase 2 from the nucleus to the cytoplasm. By this mechanism, HMGA1 modulates the transcription of p53 target genes such as Mdm2, p21waf1 , and Bax, inhibiting apoptosis. Here, we report that HMGA1 antagonizes the p53-mediated transcriptional repression of another apoptosis-related gene, Bcl-2, suggesting a novel mechanism by which HMGA1 counteracts apoptosis. Moreover, HMGA1 overexpression promotes the reduction of Brn-3a binding to the Bcl-2 promoter, thereby blocking the Brn-3a corepressor function on Bcl-2 expression following p53 activation. Consistently, a significant direct correlation between HMGA1 and Bcl-2 overexpression has been observed in human breast carcinomas harboring wild-type p53. Therefore, this study suggests a novel mechanism, based on Bcl-2 induction, by which HMGA1 overexpression contributes to the escape from apoptosis leading to neoplastic transformation. Cancer Res; 70(13); 5379-88. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of Bcl-2 Gene

et al. 2010

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“…Moreover, in ovarian carcinoma, Bcl-2 and Bcl-x L proteins are frequently overexpressed (34,(47)(48)(49) and appear to be involved in chemoresistance (34,47,(49)(50)(51). More recently, it was reported that Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells (52).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that Bcl-2 and Bcl-x L proteins are frequently overexpressed (34,(47)(48)(49) and appear to be involved in chemoresistance in ovarian carcinoma (34,47,(49)(50)(51). Furthermore, chemoresistance of ovarian carcinoma has been shown to associate with the absence of Bcl-x L expression downregulation in response to cisplatin (32,34).…”

Section: Puma Chemosensitizes Skov3 Cells By Lowering the Threshold Smentioning

confidence: 99%

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

Zhu

Cao

Chao

et al. 2011

Mol Med

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Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-x L ) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-x L downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 downregulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x L and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.

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“…Several studies have correlated BCL-2 with a survival advantage in ovarian cancer (Baekelandt et al, 1999b;Diebold et al, 1996;Henriksen et al, 1995;Herod et al, 1996) but failed to find an association with overall response to chemotherapy (Baekelandt et al, 1999b;Herod et al, 1996). In contrast, BCL-2 expression has also been reported to be associated with a poor prognosis and resistance to chemotherapy (Kassim et al, 1999;Mano et al, 1999). Since BCL-2 is thought to function as an antiapoptotic protein, a correlation between BCL-2 expression and a favourable outcome may seem paradoxical.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

Schuyer¹,

Burg²,

Henzen‐Logmans

et al. 2001

Br J Cancer

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Summary Traditional clinicopathological features do not predict which patients will develop chemotherapy resistance. The TP53 gene is frequently altered in ovarian cancer but its prognostic implications are controversial. Little is known on the impact of TP53-downstream genes on prognosis. Using molecular and immunohistochemical analyses we examined TP53 and its downstream genes p21, BAX and BCL-2 in ovarian tumour tissues and have evaluated the results in relation to clinico-pathological parameters, clinical outcome and response to platinum-based chemotherapy. Associations of tested factors and patient and tumour characteristics were studied by Spearman rank correlation and Pearsons χ 2 test. The Cox proportional hazard model was used for univariate and multivariate analysis. The associations of tested factors with response was tested using logistic regression analysis. TP53 mutation, p21 and BCL-2 expression were not associated with increased rates of progression and death. Expression of TP53 was associated with a shorter overall survival only (relative hazard rate [RHR] 2.01, P = 0.03). Interestingly, when combining TP53 mutation and expression data, this resulted in an increased association with overall survival (P = 0.008). BAX expression was found to be associated with both progression-free (RHR 0.44, P = 0.05) and overall survival (RHR 0.42, P = 0.03). Those patients who simultaneously expressed BAX and BCL-2 had a longer progression-free and overall survival compared to patients whose tumours did not express BCL-2 (P = 0.05 and 0.015 respectively). No relations were observed between tested factors and response to platinum-based chemotherapy. We conclude that BAX expression may represent a prognostic indicator for patients with ovarian cancer and that the combined evaluation of BAX and BCL-2 may provide additional prognostic significance.

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Increased bcl-2 expression is associated with primary resistance to chemotherapy in human epithelial ovarian cancer

Cited by 38 publications

References 17 publications

High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of Bcl-2 Gene

High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of Bcl-2 Gene

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

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