Li Aodi, Qu Xiujuan, Li Zhi, Qu Jinglei, Song Na, Ma Yanju, Liu Yunpeng
Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Mol Med Rep. 2015 Aug;12(2):2926-32. doi: 10.3892/mmr.2015.3676. Epub 2015 Apr 24.
Bufalin is an active compound in the traditional Chinese medicine Chan Su, which has been shown to induce apoptosis in a range of cancer cell types. However, certain gastric cancer cells are known to be resistant to bufalin. Intracellular secreted protein acidic and rich in cysteine (SPARC) regulates proliferation and apoptosis. This study aimed to evaluate the role of SPARC in bufalin-induced apoptosis in SGC7901 and MGC803 gastric cancer cells. SGC7901 cells with high SPARC expression were more resistant to bufalin than MGC803 cells with low SPARC expression. This resistance was significantly reversed by small interfering (si)RNA-mediated knockdown of SPARC. Furthermore, it was shown that SPARC negatively regulated bufalin-induced intrinsic apoptosis by protecting mitochondrial integrity, decreasing the release of cytoplasmic cytochrome c and increasing the ratio of Bcl-2/Bax. In addition, SPARC overcame bufalin-induced G2/M phase arrest by increasing levels of Cyclin B1 and Cyclin A protein expression. SPARC also activated cellular survival signals, including Src and Akt, but not extracellular signal-regulated kinase. This study demonstrated that SPARC antagonizes bufalin-induced apoptosis via inhibition of the intrinsic apoptosis pathway, inhibition of cell cycle arrest and activation of certain pathways involved in proliferation. This provides novel evidence for SPARC as a potential target by which to sensitize gastric cancer cells to bufalin.
蟾毒灵是中药蟾酥中的一种活性化合物，已被证明能诱导多种癌细胞发生凋亡。然而，某些胃癌细胞已知对蟾毒灵具有抗性。细胞内富含半胱氨酸的酸性分泌蛋白（SPARC）可调节细胞增殖和凋亡。本研究旨在评估SPARC在蟾毒灵诱导SGC7901和MGC803胃癌细胞凋亡中的作用。SPARC高表达的SGC7901细胞比SPARC低表达的MGC803细胞对蟾毒灵更具抗性。这种抗性通过小干扰（si）RNA介导的SPARC敲低而显著逆转。此外，研究表明SPARC通过保护线粒体完整性、减少细胞质细胞色素c的释放以及增加Bcl-2/Bax的比值来负向调节蟾毒灵诱导的内源性凋亡。此外，SPARC通过增加细胞周期蛋白B1和细胞周期蛋白A的蛋白表达水平来克服蟾毒灵诱导的G2/M期阻滞。SPARC还激活了包括Src和Akt在内的细胞存活信号，但未激活细胞外信号调节激酶。本研究表明，SPARC通过抑制内源性凋亡途径、抑制细胞周期阻滞以及激活某些参与增殖的途径来拮抗蟾毒灵诱导的凋亡。这为SPARC作为使胃癌细胞对蟾毒灵敏感的潜在靶点提供了新的证据。
