title: Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation.
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.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA. awhit1@med.unc.edu
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Scott C
authors.initials: SC
authors.lastname: Purinton
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Cappell
authors.forename: Jackie T
authors.initials: JT
authors.lastname: Swanik
authors.forename: Brittany
authors.initials: B
authors.lastname: Larson
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: John O
authors.initials: JO
authors.lastname: Schorge
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D034961:Antigens, Nuclear / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D034521:Nuclear Matrix-Associated Proteins / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology*
chemical_list: C485651:ACRBP protein, human; D034961:Antigens, Nuclear; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D017239:Paclitaxel