The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Abstract

Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner

“…TACC3 deficiency leads to severe growth retardation and embryonic lethality (38,40). This is in line with the anti-proliferative and cell cycle arrest/senescenceinducing impact of shRNA-mediated gene silencing of TACC3 (41,42). Moreover, it could be shown that TACC3 depletion sensitizes cells to the apoptotic and senescence-inducing effects of mitotic spindle poisons.…”

“…During the cell cycle TACC3 expression increases strongly in the G 2 /M phase (38) followed by Cdh1-dependent degradation of TACC3 during mitotic exit (39). TACC3 deficiency leads to growth retardation and embryonic lethality (38,40), in line with the anti-proliferative impact of shRNA mediated gene silencing of TACC3 (41,42).…”

Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity

“…TACC3, which is reactivated in a wide range of tumor types, is the best-characterized member of this cohort, with a demonstrated role in embryonic development and differentiation. However, with the exception of TACC3 and ACRBP, no tumorigenic role has been identified for these testis genes (2,9,15,19,33,(35)(36)(37). Given the phenotypic collaboration observed with the mitotic spindle poison paclitaxel, we first sought to determine if individual depletion of members of this cohort (FMR1NB, MAGEA5, NXF2, FSIP1, STARD6, and TACC3) leads to chromosome segregation defects in the presence of low-dose paclitaxel.…”

The clinical significance of transforming acidic coiled-coil protein 3 expression in non-small cell lung cancer

“…Yim et al identified TACC3 as a possible direct target of anti-microtubule drugs such as paclitaxel in cervical carcinoma cells (37). Subsequent studies have demonstrated that paclitaxel induces strong polyploidy and apoptosis in TACC3-depleted murine fibroblast cells and that the downregulation of TACC3 enhances paclitaxel chemosensitivity in breast carcinoma cells (38,39). However, if the expression of TACC3 in tumor tissue by immunohistochemical analysis correlates with the sensitivity to anti-microtubule drugs has not been reported yet.…”