CXC195 induces apoptosis and endoplastic reticulum stress in human hepatocellular carcinoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway

Author：

Publisher： Spandidos Publications

E-ISSN： 1791-3004|12|6|8229-8236

ISSN： 1791-2997

Source： Molecular Medicine Reports, Vol.12, Iss.6, 2015-01, pp. : 8229-8236

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Abstract

CXC195 exhibits strong protective effects against neuronal apoptosis by exerting antioxidant activity. However, the pharmacological function of CXC195 in cancer remains to be elucidated. The present study demonstrated that CXC195 exhibited significant cytotoxic effects, and induced cell cycle arrest and apoptosis in HepG2 human hepatocellular carcinoma (HCC) cell lines. Following treatment of HepG2 cells with 150 µΜ CXC195 for 24 , cell viability and the apoptotic rate were assessed using an MTT assay and Annexin V/propidium iodide staining followed by flow cytometric analysis. Molecular markers of the cell cycle, apoptosis, mitochondrial function and endoplasmic reticulum (ER) stress were analyzed by western blot or polymerase chain reaction analysis. Caspase activation, cytochrome c and apoptosisinducing factor release, and analysis of the B cell lymphoma 2 (Bcl2)associated X protein/Bcl2 ratio demonstrated that the anticancer effects of CXC195 in HepG2 cells were mediated by caspase and mitochondriadependent apoptosis. CXC195 also induced the expression of ER stressassociated proteins, including CCAATenhancerbinding protein homologous protein, and glucoseregulated proteins 94 and 78, and led to the activation of multiple branches of ER stress transducers, including inositolrequiring enzyme 1αapoptosis signalregulating kinasep38/cJun Nterminal kinase, and protein kinase Rlike endoplasmic reticulum kinaseeukaryotic translation initiation factor 2αactivating transcription factor (ATF)4 and ATF6, in the HepG2 cells. In addition, CXC195 inhibited the phosphorylation of phosphoinositide 3kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) in the HepG2 cells. These effects were enhanced following treatment with selected inhibitors of PI3K (LY294002), Akt (SH6) and mTOR (rapamycin). Furthermore, these inhibitors enhanced the proapoptotic effects of CXC195 in the HepG2 cells. In conclusion, the results of the present study indicated that CXC195 induced apoptosis and ER stress in HepG2 cells through the inhibition of the PI3K/Akt/mTOR signaling pathway.