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Abstract Background ZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response. Results We provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation in vitro associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells. Conclusion Altogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects.

Abstract: We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment. [Copyright &y& Elsevier]

Background: 2-Deoxy-D-glucose (2-DG) is an analog of glucose that is preferentially captured by tumors and is accumulated in transformed cells, because the phosphorylated molecule (2-DG-6P) cannot be metabolized or diffused outside the cells. Targeted with a fluorine atom, 18F-DG is currently used to visualize malignant tumors (PET scan). Although cancer cells have been reported to be strongly dependent on glycolysis (Warburg effect), very few reports have studied the inhibitory effects of 2-DG on cancer., Materials and Methods: Our objective was to study, in a large panel of human malignant cells of various origins (ovarian, squamous, cerebral, hepatic, colonic and mesothelial), if the inhibitory activity of 2DG against tumor growth could be considered a general phenomenon and to determine its effect on the cell cycle., Results: Four types of response in the different cell lines were observed when cells were cultured in the presence of 2-DG (5 mM) continuous exposure: proliferation slow down; proliferation arrest without signs of apoptosis; strong cell cycle arrest accompanied by moderate apoptosis induction; massive apoptosis., Conclusion: 2-DG appears as an interesting new therapeutic agent against cancer in vitro, and should be tested in in vivo studies.