Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity
Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity
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DOI：
10.1128/mcb.00686-12
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发表时间：
2012-10-01
影响因子：
5.3
通讯作者：
Whitehurst, Angelique W.
中科院分区：
文献类型：
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作者：
Cappell, Kathryn M.;Sinnott, Rebecca;Whitehurst, Angelique W.
虽然通常参与精子发生的基因的表达在肿瘤中经常被检测到，但这些基因产物在肿瘤行为中所需的程度尚不清楚。为了开始阐明它们与肿瘤发生的功能相关性，我们鉴定了一组在非小细胞肺癌中显示紫杉醇合成致死性的蛋白质，并且其表达偏向于睾丸和肿瘤。值得注意的是，这些睾丸蛋白质，FMR1NB，NXF2，MAGEA5，FSIP1和STARD6，是肿瘤细胞中精确染色体分离所必需的。它们的个体消耗增强了多极纺锤体的产生，增加了有丝分裂的通过时间，并诱导微核形成，以响应其他无害剂量的紫杉醇。异常有丝分裂的潜在基础是微管功能的改变，因为它们的消耗增加了微管细胞器的形成并破坏了微管的稳定性。鉴于这些观察结果，我们假设重新激活的睾丸蛋白可能代表独特的肿瘤细胞脆弱性，如果有针对性，可以增强抗有丝分裂治疗的反应性。事实上，我们证明，紫杉醇与配子发生和肿瘤细胞有丝分裂蛋白TACC3的小分子抑制剂相结合，导致增强的中心体异常，激活死亡程序，和锚定非依赖性生长的损失。
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.