Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity
Year: 2012
Type: article
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.
Source: Molecular and Cellular Biology
DOI: 10.1128/mcb.00686-12
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: Harnessing Functional Genomics to Reveal Cancer Specific Determinants of Mitosis, Medical Scientist Training Program, G4546178636, G5944917958, Predoctoral Training in Pharmacological Sciences, G695913448, Harnessing Functional Genomics to Reveal Cancer Specific Determinants of Mitosis, G7815700167, Mechanistic Elaboration of Fragility in the Cancer Cell Mitotic Spindle, Cancer Center Support Grant, Cancer Cell Biology Training Program
OpenAlex ID: W2099255652