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Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner.
Gynecol Oncol. 2006 Aug; 102(2):348-55.GO

Abstract

OBJECTIVE

Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis.

METHODS AND RESULTS

Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection.

CONCLUSION

Taken together, these data suggest that PTEN over-expression may represent a novel therapeutic approach for chemoresistant human ovarian cancer and that this may involve a p53-mediated apoptotic cascade independent of the PI3K/Akt pathway.

Authors+Show Affiliations

Reproductive Biology Unit and Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada, K1Y 4E9.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16545436

Citation

Yan, Xiaojuan, et al. "Over-expression of PTEN Sensitizes Human Ovarian Cancer Cells to Cisplatin-induced Apoptosis in a P53-dependent Manner." Gynecologic Oncology, vol. 102, no. 2, 2006, pp. 348-55.
Yan X, Fraser M, Qiu Q, et al. Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecol Oncol. 2006;102(2):348-55.
Yan, X., Fraser, M., Qiu, Q., & Tsang, B. K. (2006). Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecologic Oncology, 102(2), 348-55.
Yan X, et al. Over-expression of PTEN Sensitizes Human Ovarian Cancer Cells to Cisplatin-induced Apoptosis in a P53-dependent Manner. Gynecol Oncol. 2006;102(2):348-55. PubMed PMID: 16545436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. AU - Yan,Xiaojuan, AU - Fraser,Michael, AU - Qiu,Qing, AU - Tsang,Benjamin K, Y1 - 2006/03/20/ PY - 2005/09/07/received PY - 2005/12/19/revised PY - 2005/12/29/accepted PY - 2006/3/21/pubmed PY - 2006/8/30/medline PY - 2006/3/21/entrez SP - 348 EP - 55 JF - Gynecologic oncology JO - Gynecol. Oncol. VL - 102 IS - 2 N2 - OBJECTIVE: Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis. METHODS AND RESULTS: Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection. CONCLUSION: Taken together, these data suggest that PTEN over-expression may represent a novel therapeutic approach for chemoresistant human ovarian cancer and that this may involve a p53-mediated apoptotic cascade independent of the PI3K/Akt pathway. SN - 0090-8258 UR - https://www.unboundmedicine.com/medline/citation/16545436/Over_expression_of_PTEN_sensitizes_human_ovarian_cancer_cells_to_cisplatin_induced_apoptosis_in_a_p53_dependent_manner_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(06)00021-7 DB - PRIME DP - Unbound Medicine ER -