Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorineinduced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC.
Hepatocellular carcinoma (HCC) is well-known to be a highly prevalent malignant tumor, but the treatment of this pathological state has been still challenging. Solamargine (SM), a traditional Chinese herb-derived compound, has been widely reported to possess multiple antitumor properties. However, whether SM plays a vital role in HCC therapy and how it exerts an antitumor effect remains unclear. Thus, in this study, we demonstrated that SM inhibited the proliferation of HCC and effectively induced HCC cell apoptosis and autophagy in vitro and in vivo. Mechanistically, the oncogenic factor LIF was aberrantly elevated in HCC tissues and down-regulated by SM in HCC cells, as well as subsequently the overexpression of LIF could restore the anti-HCC effects of SM via miR-192-5p/CYR61/Akt signaling pathways. Additionally, SM could repolarize tumor associated macrophages by LIF/p-Stat3 to inhibit the growth and epithelial-mesenchymal transition of HCC, and simultaneously affected other immune cell populations in the immune (tumor) microenvironment by regulating macrophages, such as MDSCs, DCs and T cell populations. Together, these findings exploit the potential use of SM against HCC and shed light on exploring SM as a potent candidate drug for the future HCC therapeutics.
Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.
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