Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation

Angelique W. Whitehurst, Yang Xie, Scott C. Purinton, Kathryn M. Cappell, Jackie T. Swanik, Brittany Larson, Luc Girard, John O. Schorge, Michael A. White

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Cancer cells manage to divide in the context of gross chromosomal abnormalities. These abnormalities can promote bypass of normal restraints on cell proliferation but at a cost of mitotic vulnerabilities that can be attacked by chemotherapy. Determining how cancer cells balance these issues may permit chemotherapeutic sensitivity to be leveraged more efficiently. From a pan-genomic small interfering RNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen acrosin binding protein (ACRBP)/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP expression is normally restricted to the testes but is detected in a wide variety of cancers, including most ovarian cancers. We found that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Moreover, high ACRBP expression correlated with reduced survival time and faster relapse among ovarian cancer patients. We identified the mitotic spindle protein NuMA as an ACRBP-interacting protein that could account for the effects of ACRBP on paclitaxel sensitivity. In cancer cells, ACRBP restricted a NuMA-dependent abrogation of a mitotic spindle assembly that is otherwise pathologic. As a consequence, ACRBP depletion resulted in mitotic errors and reduced proliferative fitness that could be rescued by NuMA codepletion. We propose that the codependent relationship of ACRBP and NuMA in cancer cells reflects their passage through a selection bottleneck during tumor evolution, one which requires the acquisition of traits that normalize mitotic perturbations that originally drove the plasticity of a preneoplastic genome. The molecular definition of such traits as defined by the ACRBP-NuMA complex may represent conceptually ideal intervention targets based on the wide therapeutic windows they may offer.

Original languageEnglish (US)
Pages (from-to)7652-7661
Number of pages10
JournalCancer research
Volume70
Issue number19
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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