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ABT-737 is a small molecule Bcl-2 homology (BH)-3 domainmimetic that binds to the Bcl-2 family proteins Bcl-2 and Bcl-xL and is currently under investigation in the clinic. In this study, we investigated potential mechanisms of resistance to ABT-737 in leukemia cell lines. Compared with parental cells, cells that have developed acquired resistance to ABT-737 showed increased expression of Mcl-1 in addition to posttranslational modifications that facilitated both Mcl-1 stabilization and its interaction with the BH3-only protein Bim. To sensitize resistant cells, Mcl-1 was targeted by two pan--Bcl-2 family inhibitors, obatoclax and gossypol. Although gossypol was effective only in resistant cells, obatoclax induced cell death in both parental and ABT-737--resistant cells. NOXA levels were increased substantially by treatment with gossypol and its expression was critical for the gossypol response. Mechanistically, the newly generated NOXA interacted with Mcl-1 and displaced Bim from the Mcl-1/Bim complex, freeing Bim to trigger the mitochondrial apoptotic pathway. Together, our findings indicate that NOXA and Mcl-1 are critical determinants for gossypol-mediated cell death in ABT-737--resistant cells. These data therefore reveal novel insight into mechanisms of acquired resistance to ABT-737. [ABSTRACT FROM AUTHOR]

Epithelial ovarian carcinoma (EOC) is the most prevalent form of ovarian cancer in the United States, representing approximately 85% of all cases and causing more deaths than any other gynecologic malignancy. We propose that optimized control of EOC requires the incorporation of a vaccine capable of inducing safe and effective preemptive immunity in cancer-free women. In addition, we hypothesize that ovarian-specific self-proteins that are "retired" from autoimmune-inducing expression levels as ovaries age but are expressed at high levels in emerging EOC may serve as vaccine targets for mediating safe and effective primary immunoprevention. Here, we show that expression of the extracellular domain of anti-Müllerian hormone receptor II (AMHR2-ED) in normal tissues is confined exclusively to the human ovary, drops to nonautoimmune inducing levels in postmenopausal ovaries, and is at high levels in approximately 90% of human EOC. We found that AMHR2-ED vaccination significantly inhibits growth of murine EOC and enhances overall survival without inducing oophoritis in aged female mice. The observed inhibition of EOC growth was mediated substantially by induction of AMHR2-ED-specific IgG antibodies that agonize receptor signaling of a Bax/caspase-3-dependent proapoptotic cascade. Our results indicate that AMHR2-ED vaccination may be particularly useful in providing safe and effective preemptive immunity against EOC in women at high genetic or familial risk who have the greatest need for a preventive vaccine and ultimately in cancer-free postmenopausal women who account for 75% of all EOC cases. Cancer Prev Res; 10(11); 612-24. ©2017 AACR See related editorial by Shoemaker et al., p. 607 ., (©2017 American Association for Cancer Research.)

The retinoblastoma (pRb), p107, and p130 pocket proteins bind to the E2F transcription factors to control gene expression. E2F4 protein levels increased and accumulated in the nuclei of prostate carcinoma cells subjected to ionizing radiation (IR). The IR-induced increase of E2F4 levels led to an increase in E2F4 binding to p130 but had no effect on E2F4/p107 or E2F5/p130 complexes. The increase in E2F4/p130 association after IR was observed in prostate carcinoma cells regardless of their sensitivity to androgens, but not in breast carcinoma cells. E2F4/p130 complex formation was dependent on dissociation of p130 from cyclin-dependent kinase 2 and p130 dephosphorylation. Disruption of E2F4 through small interfering RNA prevented p130/E2F4 complex formation and sensitized cells to IR-induced apoptosis, leading to caspase-3 activation, cleavage of its substrate, poly(ADP-ribose) polymerase, and nuclear condensation. The E2F4/p130 pocket protein complex emerges as a new target of radiation in prostate carcinoma cells.