Aurora kinase A inhibition induces synthetic lethality in SMAD4-deficient colorectal cancer cells via spindle assembly checkpoint activation

作者全名："Shi, Changxiang; Tao, Shishi; Ren, Guowen; Yang, Eun Ju; Shu, Xiaodong; Mou, Pui Kei; Liu, Yifan; Dang, Yongjun; Xu, Xiaoling; Shim, Joong Sup"

作者地址："[Shi, Changxiang; Tao, Shishi; Ren, Guowen; Yang, Eun Ju; Shu, Xiaodong; Mou, Pui Kei; Liu, Yifan; Xu, Xiaoling; Shim, Joong Sup] Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macau, Peoples R China; [Shi, Changxiang; Tao, Shishi; Ren, Guowen; Yang, Eun Ju; Shu, Xiaodong; Mou, Pui Kei; Liu, Yifan; Xu, Xiaoling; Shim, Joong Sup] Univ Macau, MOE Frontiers Sci Ctr Precis Oncol, Taipa, Macau, Peoples R China; [Shi, Changxiang] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Womens Hosp, Nanjing Matern & Child Hlth Care Inst, Nanjing, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing, Peoples R China"

通信作者："Shim, JS (通讯作者)，Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macau, Peoples R China.; Shim, JS (通讯作者)，Univ Macau, MOE Frontiers Sci Ctr Precis Oncol, Taipa, Macau, Peoples R China."

来源：ONCOGENE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000779227700002

JCR分区：Q1

影响因子：8

年份：2022

卷号：41

期号：19

开始页：2734

结束页：2748

文献类型：Article

关键词：　

摘要："SMAD4 loss-of-function mutations have been frequently observed in colorectal cancer (CRC) and are recognized as a drug target for therapeutic exploitation. In this study, we performed a synthetic lethal drug screening with SMAD4-isogenic CRC cells and found that aurora kinase A (AURKA) inhibition is synthetic lethal with SMAD4 loss. Inhibition of AURKA selectively inhibited the growth of SMAD4(-/-) CRC in vitro and in vivo. Mechanistically, SMAD4 negatively regulated AURKA level, resulting in the significant elevation of AURKA in SMAD4(-/-) CRC cells. Inhibition of AURKA induced G(2)/M cell cycle delay in SMAD4(+/+) CRC cells, but induced apoptosis in SMAD4(-/-) CRC cells. We further observed that a high level of AURKA in SMAD4(-/-) CRC cells led to abnormal mitotic spindles, leading to cellular aneuploidy. Moreover, SMAD4(-/-) CRC cells expressed high levels of spindle assembly checkpoint (SAC) proteins, suggesting the hyperactivation of SAC. The silencing of key SAC proteins significantly rescued the AURKA inhibition-induced cell death in SMAD4(-/-) cells, suggesting that SMAD4(-/-) CRC cells are hyper-dependent on AURKA activity for mitotic exit and survival during SAC hyperactivation. This study presents a unique synthetic lethal interaction between SMAD4 and AURKA and suggests that AURKA could be a potential drug target in SMAD4-deficient CRC."

基金机构："Science and Technology Development Fund, Macau SAR [FDCT/0107/2020/A, FDCT/0030/2020/A]; Multi-Year Research Grant, University of Macau [MYRG2019-00116-FHS, MYRG2020-00229-FHS]"

基金资助正文："This study was supported by Science and Technology Development Fund, Macau SAR (FDCT/0107/2020/A and FDCT/0030/2020/A to JSS), and the Multi-Year Research Grant, University of Macau (MYRG2019-00116-FHS and MYRG2020-00229-FHS to JSS)."