Kahweol Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting the Src/mTOR/STAT3 Signaling Pathway.
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ABSTRACT:
SUBMITTER: Seo HY
PROVIDER: S-EPMC8508869 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study explored the effects of Hugan Buzure (HBR) on cell apoptosis and autophagy in hepatocellular carcinoma (HCC) and the molecular mechanisms of the PI3K/Akt/mTOR signaling pathway. HepG2 and Huh7 cell viability was detected by the tetramethylazolium salt colorimetric (MTT) method. Cell proliferation was measured using the colony formation method. Hoechst 33258 staining and flow cytometry were employed to detect apoptosis. In addition, immunofluorescence was carried out to evaluate the expression of LC3. Western blot was performed to detect the expression of Bcl-2, Bax, Caspase-3, LC3, Beclin1, p62 (SQSTM1), and PI3K/Akt/mTOR signal pathway-related proteins in HCC cells. This work verified that HBR reduced HepG2 and Huh7 cell proliferation in a concentration-dependent manner. Treatment with HBR caused an obvious improvement of the apoptosis rate, accompanied by the increase in Bax/Bcl2, Caspase3, LC3II, and Beclin1 levels, respectively. Furthermore, HBR downregulated the expression of p62, p-PI3K, p-Akt, and p-mTOR proteins. HBR combined with HCQ enhanced HBR-induced apoptosis. In conclusion, HBR induced autophagy and apoptosis through PI3K/Akt/mTOR signaling pathway, leading to HCC cell death. This research preliminarily suggested the potential role of HBR in the treatment of HCC.
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Project description:Hepatocellular carcinoma (HCC) is an aggressive malignancy with high rates of metastasis and relapse. Isoquercitrin (ISO), a natural flavonoid present in the Chinese bayberry and other plant species, reportedly exerts notable inhibitory effects on tumor cell proliferation, though the mechanism is unknown. In the present study, we exposed HepG2 and Huh7 human liver cancer cells to ISO and examined the roles of autophagy and apoptosis in ISO-mediated cell death. We found that ISO exposure inhibited cell viability and colony growth, activated apoptotic pathway, and triggered dysregulated autophagy by activating the AMPK/mTOR/p70S6K pathway. Autophagy inhibition using 3-methyladenine (3-MA) or Atg5-targeted siRNA decreased the Bax/Bcl-2 ratio, caspase-3 activation, and PARP cleavage and protected cells against ISO-induced apoptosis. Moreover, autophagy inhibition reversed the upregulation of AMPK phosphorylation and downregulation of mTOR and p70S6K phosphorylation elicited by ISO. By contrast, application of a broad-spectrum caspase inhibitor failed to inhibit autophagy in ISO-treated cells. These data indicate that ISO simultaneously induced apoptosis and autophagy, and abnormal induction of autophagic flux contributed to ISO-triggered caspase-3-dependent apoptosis.
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Project description:BackgroundHepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear.MethodsWe used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1In vivo experiments were performed to verify the conclusions from the in vitro experiments.ResultsOur data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro experiments. in vivo experiments were performed to verify the conclusions from the α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1.ConclusionsThe results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1.
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Project description:Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.
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Project description:AimsIsoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, has previously been reported to have anti-tumor effects in vivo and in vitro. However, the mechanisms whereby ISL exerts its anticancer effects remain poorly understood in hepatocellular carcinoma (HCC).PurposeIn the present study, we investigated the anticancer efficacy and associated mechanisms of ISL in HCC MHCC97-H and SMMC7721 cells.ResultsWe found that ISL inhibited cell viability and proliferation and induced apoptosis in a dose- and time-dependent manner in liver cancer lines. Furthermore, ISL could activate autophagy in HCC cells, and the autophagy inhibitor HCQ enhances ISL-induced apoptosis in HCC cells. Additionally, ISL induced apoptosis and autophagy through inhibition of the PI3K/Akt/mTOR pathway. Most importantly, in a xenograft tumor model in nude mice, data showed that the administration of ISL decreased tumor growth and concurrently promoted the expression of LC3-II and cleaved-caspase-3. Interestingly, we found that ISL inhibits mTOR by docking onto the ATP-binding pocket of mTOR (ie, it competes with ATP). We thus suggest that mTOR is a potential target for ISL inhibition of hepatocellular carcinoma development, which could be of interest for future investigations.ConclusionTaken together, the results reveal that ISL effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction in vivo and in vitro, probably via the PI3K/Akt/mTOR pathway. ISL may be a potential therapeutic agent for hepatocellular carcinoma.
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Project description:Polyphyllin II (PPII) is a natural steroidal saponin occurring in Rhizoma Paridis. It has been demonstrated to exhibit anti-cancer activity against a variety of cancer cells. However, the anti-colorectal cancer (CRC) effects and mechanism of action of PPII are rarely reported. In the present study, we showed that PPII inhibited the proliferation of HCT116 and SW620 cells. Moreover, PPII induced G2/M-phase cell cycle arrest and apoptosis, as well as protective autophagy, in CRC cells. We found that PPII-induced autophagy was associated with the inhibition of PI3K/AKT/mTOR signaling. Western blotting results further revealed that PPII lowered the protein levels of phospho-Src (Tyr416), phospho-JAK2 (Tyr1007/1008), phospho-STAT3 (Tyr705), and STAT3-targeted molecules in CRC cells. The overactivation of STAT3 attenuated the cytotoxicity of PPII against HCT116 cells, indicating the involvement of STAT3 inhibition in the anti-CRC effects of PPII. PPII (0.5 mg/kg or 1 mg/kg, i.p. once every 3 days) suppressed HCT116 tumor growth in nude mice. In alignment with the in vitro results, PPII inhibited proliferation, induced apoptosis, and lowered the protein levels of phospho-STAT3, phospho-AKT, and phospho-mTOR in xenografts. These data suggest that PPII could be a potent therapeutic agent for the treatment of CRC.
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Project description:Lenvatinib has become the first-line therapy in advanced hepatocellular carcinoma (HCC), but its efficacy is still limited because of the inevitable development of resistance. It has been reported that cellular cholesterol levels are associated with tyrosine kinase inhibitor (TKI) efficacy. Here, we show that betulin, a sterol regulatory element-binding protein 2 (SREBP2) inhibitor, markedly enhances the anti-tumor effect of lenvatinib in HCC both in vitro and in vivo. Our results also show that the combination treatment of lenvatinib and betulin synergistically inhibits the proliferation and clonogenicity of HCC cells. The mRNA and protein expressions of IL-1β are markedly decreased in HCC cells treated with betulin, while the sensitivity of HCC cells to lenvatinib is enhanced. Moreover, we find that the knockdown of IL-1β also enhances the efficacy of lenvatinib, and recombinant IL-1β protein rescues cell viability, which is reduced by lenvatinib in HCC cells. Further mechanistic studies indicate that betulin decreases the level of IL-1β in HCC cells by inhibiting the mTOR signaling pathway. Finally, the growth of the tumors in xenograft mouse models subjected to combination treatment is significantly suppressed. In summary, our study reveals that the SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway, which may be a promising therapeutic strategy for patients with HCC.
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Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally. Because most patients are diagnosed at advanced stages of the disease, multi-targeted tyrosine kinase inhibitor sorafenib is the only available drug to show limited effectiveness. Novel and effective therapies are unmet medical need for advanced HCC patients. Given that the aberrant expression and activity of platelet-derived growth factor receptor α (PDGFRα) are closely associated with the pathogenesis of HCC, here we present the discovery and identification of a novel PDGFRα inhibitor, N-(3-((4-(benzofuran-2-yl)pyrimidin-2-yl)oxy)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (E5) after comparison of different derivatives. We found that E5 inhibited proliferation and induced apoptosis in HCC cells. Since the pan-caspase inhibitor Z-VAD-FMK partially rescued HCC cells from E5-reduced cell viability, autophagic cell death triggered by E5 was subsequently investigated. E5 could induce the conversion of LC3-I to LC3-II, increase the expression of Atg5 and restore the autophagy flux blocked by chloroquine. Meanwhile, E5 was able to downregulate the PDGFRα/PI3K/AKT/mTOR pathway and to activate MAPK/ERK signaling pathway. Taken together, in addition to the possibility of E5 as a valuable drug candidate, the present study further supports the notion that targeted inhibition of PDGFRα is a promising therapeutic strategy for HCC.
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