Chang Jun, Hong Ling, Liu Yaozhong, Pan Yiwen, Yang Hao, Ye Wenrui, Xu Keli, Li Zhijian, Zhang Shubing
Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, People's Republic of China.
Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, People's Republic of China.
Cancer Manag Res. 2020 Apr 20;12:2641-2651. doi: 10.2147/CMAR.S250171. eCollection 2020.
Molecular targeting is a powerful approach for aggressive claudin-low breast cancer (CLBC). Overexpression of PI3K catalytic subunit gamma (PIK3CG) in human CLBC is offering a promising opportunity for targeted therapies. We utilized a specific inhibitor of PIK3CG combined with paclitaxel (PTX) to treat CLBC cells in vitro and in vivo.
The tumor cells growth and apoptosis in vitro were analyzed by CCK8, plate clone formation assay, tumorsphere assay, Hoechst staining and flow cytometry. The invasion and metastasis ability of tumor cells in vitro were investigated by wound healing and transwell experiments. Critical gene expression levels were checked by qRT-PCR and Western blot. Xenograft models with CLBC cell lines in SCID mice were established to investigate the effect of combined drugs in vivo.
We identified that PIK3CG was a potential therapeutic target for CLBC patients. Targeting PIK3CG potentiated CLBC cells growth inhibition in 2D and 3D cultures by PTX. Inhibition of PIK3CG activation could enhance CLBC cells apoptosis and migration suppression induced by PTX. Manipulating autophagy was a validated approach for the use of PIK3CG inhibitor. Using CLBC xenograft mice model, we found that CLBC tumors in vivo could be well treated by combined drugs of PIK3CG inhibitor and PTX.
We demonstrated that PIK3CG was a potential target for the therapy of CLBC and inhibition of PIK3CG activation could reinforce the therapeutic effect of this aggressive disease by PTX. The combined use of PIK3CG inhibitor and PTX might be a potential regimen for treating this subtype of breast cancer.
分子靶向治疗是侵袭性低Claudin表达型乳腺癌（CLBC）的一种有效方法。人CLBC中PI3K催化亚基γ（PIK3CG）的过表达为靶向治疗提供了一个有前景的机会。我们使用PIK3CG的特异性抑制剂联合紫杉醇（PTX）在体外和体内治疗CLBC细胞。
通过CCK8、平板克隆形成试验、肿瘤球试验、Hoechst染色和流式细胞术分析体外肿瘤细胞的生长和凋亡。通过伤口愈合试验和Transwell实验研究体外肿瘤细胞的侵袭和转移能力。通过qRT-PCR和蛋白质免疫印迹法检测关键基因的表达水平。建立SCID小鼠CLBC细胞系异种移植模型，研究联合用药在体内的效果。
我们确定PIK3CG是CLBC患者的一个潜在治疗靶点。靶向PIK3CG可增强PTX在二维和三维培养中对CLBC细胞生长的抑制作用。抑制PIK3CG激活可增强PTX诱导的CLBC细胞凋亡和迁移抑制。调控自噬是使用PIK3CG抑制剂的一种有效方法。使用CLBC异种移植小鼠模型，我们发现PIK3CG抑制剂和PTX联合用药能很好地治疗体内的CLBC肿瘤。
我们证明PIK3CG是CLBC治疗的一个潜在靶点，抑制PIK3CG激活可增强PTX对这种侵袭性疾病的治疗效果。PIK3CG抑制剂和PTX联合使用可能是治疗这种亚型乳腺癌的一种潜在方案。
