Wenfeng Zhang1, Jie Xu2,3, Dexiang Ji4, Zhangyun Li5, Wenxing He6, Fei Yang7, Huiyin Lan7, Yu Wang8, Zhengping Wu1, Xiaoshan Liu1, Shanhua Huang1, Longkun Li3, Weihua Zhou2. 1. Department of Infectious Disease, the First Affiliated Hospital, Nanchang University, Nanchang, China. 2. Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China. 3. Department of Urology, the Second Affiliated Hospital, Third Military Medical University, Chongqing, China. 4. Department of Hematology, the First Affiliated Hospital, Nanchang University, Nanchang, China. 5. Department of Oncology, the Third Hospital of Nanchang, Nanchang, China. 6. Department of Breast Surgery, Jiangxi Province Tumor Hospital, Nanchang, China. 7. Institute of Translational Medicine, Zhejiang University, Hangzhou, China. 8. Department of Nephrology, the First Affiliated Hospital, Nanchang University, Nanchang, China.
Abstract
BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.
BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancerpatients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.