Gong Chen, Liao Hui, Wang Jiang, Lin Yang, Qi Jun, Qin Liang, Tian Lin-Qiang, Guo Feng-Jing
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Asian Pac J Cancer Prev. 2012;13(7):3103-7. doi: 10.7314/apjcp.2012.13.7.3103.
Osteosarcoma, the most common primary mesenchymal malignant tumor, usually has bad prognosis in man, with cancer stem-like cells (CSCs) considered to play a critical role in tumorigenesis and drug-resistance. It is known that phosphatidylinositol 3-kinase (PI3K) is involved in regulation of tumor cell fates, such as proliferation, cell cycling, survival and apoptosis. Whether and how PI3K and inhibitors might cooperate in human osteosarcoma CSCs is still unknown. We therefore evaluated the effects of LY294002, a PI3K inhibitor, on the cell cycle and apoptosis of osteosarcoma CSCs in vitro. LY294002 prevented phosphorylation of protein kinase B (PKB/Akt) by inhibition of PI3K phosphorylation activity, thereby inducing G0/G1 cell cycle arrest and apoptosis in osteosarcoma CSCs. Further studies also demonstrated that apoptosis induction by LY294002 is accompanied by activation of caspase-9, caspase-3 and PARP, which are involved in the mitochondrial apoptosis pathway. Therefore, our results indicate PI3K inhibitors may represent a potential strategy for managing human osteosarcoma via affecting CSCs.
骨肉瘤是最常见的原发性间充质恶性肿瘤，在人类中通常预后不良，癌干细胞（CSCs）被认为在肿瘤发生和耐药性中起关键作用。已知磷脂酰肌醇3激酶（PI3K）参与调节肿瘤细胞命运，如增殖、细胞周期、存活和凋亡。PI3K及其抑制剂在人类骨肉瘤癌干细胞中是否以及如何协同作用仍不清楚。因此，我们在体外评估了PI3K抑制剂LY294002对骨肉瘤癌干细胞细胞周期和凋亡的影响。LY294002通过抑制PI3K磷酸化活性来阻止蛋白激酶B（PKB/Akt）的磷酸化，从而诱导骨肉瘤癌干细胞的G0/G1期细胞周期停滞和凋亡。进一步的研究还表明，LY294002诱导的凋亡伴随着参与线粒体凋亡途径的半胱天冬酶-9、半胱天冬酶-3和聚（ADP-核糖）聚合酶（PARP）的激活。因此，我们的结果表明，PI3K抑制剂可能是通过影响癌干细胞来治疗人类骨肉瘤的一种潜在策略。
