Abstract
Abstract Tumor cells can undergo a productive mitosis despite the wholesale presence of chromosomal aberrations. While this behavior may generate plasticity with respect to the acquisition of tumorigenic traits, it also represents a vulnerability for therapeutic intervention. Using a whole genome siRNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen ACRBP/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP is as a cancer-testis antigen, a class of genes whose expression is selective to the testes but frequently activated in a wide range of tumors. Scant functional data exists on the contribution of CT-antigens to tumorigenic phenotypes. Here, we find that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Furthermore, depletion of ACRBP significantly sensitizes ovarian tumor cells to paclitaxel in an orthotopic xenograft model system. We identified the mitotic spindle component NuMA as an ACRBP-interacting protein that may account for the effects of ACRBP on paclitaxel sensitivity. In particular, ACRBP depletion results in mitotic errors and reduced proliferative fitness that can be rescued by NuMA co-depletion. ACRBP appears to modulate NuMA protein levels, potentially by regulating its post-translational modifications. Remarkably, NuMA overexpression, a frequent event in tumors, is sufficient to induce expression of ACRBP. We propose that activation of ACRBP is positively selected for during tumor evolution to buttress mitotic spindle fidelity and chromosome segregation. Identification and elaboration of elements of the genome that are subverted to support essential cell biological processes in tumor cells present new therapeutic opportunities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-364. doi:1538-7445.AM2012-LB-364
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