title: Multiple cancer testis antigens function to support tumor cell mitotic fidelity.
abstract: While the expression of genes that are normally involved in spermatogenesis is frequently detected in tumors, the extent to which these gene products are required for neoplastic behaviors is unclear. To begin to address their functional relevance to tumorigenesis, we identified a cohort of proteins which display synthetic lethality with paclitaxel in non-small-cell lung cancer and whose expression is biased toward testes and tumors. Remarkably, these testis proteins, FMR1NB, NXF2, MAGEA5, FSIP1, and STARD6, are required for accurate chromosome segregation in tumor cells. Their individual depletion enhances the generation of multipolar spindles, increases mitotic transit time, and induces micronucleation in response to an otherwise innocuous dose of paclitaxel. The underlying basis for abnormal mitosis is an alteration in microtubule function, as their depletion increases microtubule cytaster formation and disrupts microtubule stability. Given these observations, we hypothesize that reactivated testis proteins may represent unique tumor cell vulnerabilities which, if targeted, could enhance responsiveness to antimitotic therapy. Indeed, we demonstrate that combining paclitaxel with a small-molecule inhibitor of the gametogenic and tumor cell mitotic protein TACC3 leads to enhanced centrosomal abnormalities, activation of death programs, and loss of anchorage-independent growth.
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Cappell
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sinnott
authors.forename: Patrick
authors.initials: P
authors.lastname: Taus
authors.forename: Kimberly
authors.initials: K
authors.lastname: Maxfield
authors.forename: Moriah
authors.initials: M
authors.lastname: Scarbrough
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects / Q000502:physiology; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D029589:Seminal Plasma Proteins / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C552592:FSIP1 protein, human; C095204:MAGEA4 protein, human; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; C473333:NY-SAR-35 antigen, human; D009363:Neoplasm Proteins; C456545:STARD6 protein, human; D029589:Seminal Plasma Proteins; C120551:TACC3 protein, human; C542434:cancer testis antigen NXF2, human; D017239:Paclitaxel