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

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 apoptosis‑inducing factor release, and analysis of the B cell lymphoma 2 (Bcl‑2)‑associated X protein/Bcl‑2 ratio demonstrated that the anticancer effects of CXC195 in HepG2 cells were mediated by caspase and mitochondria‑dependent apoptosis. CXC195 also induced the expression of ER stress‑associated proteins, including CCAAT‑enhancer‑binding protein homologous protein, and glucose‑regulated proteins 94 and 78, and led to the activation of multiple branches of ER stress transducers, including inositol‑requiring enzyme 1α‑apoptosis signal‑regulating kinase‑p38/c‑Jun N‑terminal kinase, and protein kinase R‑like endoplasmic reticulum kinase‑eukaryotic translation initiation factor 2α‑activating transcription factor (ATF)4 and ATF6, in the HepG2 cells. In addition, CXC195 inhibited the phosphorylation of phosphoinositide 3‑kinase (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 (SH‑6) and mTOR (rapamycin). Furthermore, these inhibitors enhanced the pro‑apoptotic 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.

Effects of endoplasmic reticulum stress on autophagy and apoptosis of human leukemia cells via inhibition of the PI3K/AKT/mTOR signaling pathway

“…In this sense, ERS may induce autophagy and apoptosis via the suppression of mTOR (26). Chen et al reported similar results to the present study and identified a causal relationship between ERS and autophagy-mediated apoptosis in human hepatocellular carcinoma cell lines with the aid of PI3K/AKT/mTOR signaling pathway inhibition (27).…”

MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation

“…Previous studies demonstrated that mTOR pathways, including pRPS6, p-AKT, IGF-1R and RICTOR are up-regulated in 40-50% of HCCs, highlighting its importance in HCC [26]. Additionally, inhibition of mTOR signaling has been reported to sensitize tumor cells to apoptosis induced by several anticancer agents [27,28]. Here we find that the upregulation of miR-223 could suppress the expression of its target gene Rab1, which can inhibit mTOR pathway activation, and leads to enhancement of miR-223-regulated cell death and apoptosis in HCC cells.…”

Down-regulation of CHERP inhibits neuroblastoma cell proliferation and induces apoptosis through ER stress induction

“…Numerous lines of evidence have shown that ER stress (ERS) can up-regulate DR5 expression, and this process plays an important role in the initiation of apoptosis of human cancer cells [ 24 , 25 ]. Additionally, activation of ER stress can inhibit the AKT/mTOR signaling pathway in numerous types of tumor cells [ 26 – 28 ]. Mammalian target of rapamycin (mTOR) is commonly activated in multiple tumors and forms two multiprotein complexes, mTORC1 and mTORC2, that control various cellular processes, including cell proliferation, metabolism, invasion, and autophagy [ 29 – 33 ].…”