Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

Abstract

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.

Lycorine Suppresses Endplate-Chondrocyte Degeneration and Prevents Intervertebral Disc Degeneration by Inhibiting NF-κB Signalling Pathway

“…Lycorine is extensively studied as an anti-tumour drug and has been demonstrated to have effects on the induction of cell apoptosis [72-77], autophagy [78] and cell cycle arrest [79, 80] in different tumour cell lines. Thus, in the present study, the toxicity of lycorine on endplate cells was carefully assessed, and we found that CEP cells showed no obvious apoptosis or cycle arrest effect at 0.4 µM LY, as this dose is much lower than the anti-tumour effect dose (4-50 µM) used in previous studies.…”

Lycorine: A prospective natural lead for anticancer drug discovery

“…Apart from the above mention effects of lycorine, it can also modulate several signaling pathways to regulate growth and proliferation of cancer cells. These include the JNK pathway [69], the phosphor-Akt pathway [71,123], the MEK/ERK pathway [66] and the JAK/STAT signaling pathway [67].…”

7‐Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma

“…Our previous studies have demonstrated that lycorine‐promoted autophagy and apoptosis inhibit the growth of HCC cells. Disruption of autophagy markedly enhances the apoptotic effect by facilitating the switch from autophagy to apoptosis, thus further augmenting antitumor effects . Therefore, the role of autophagy in cell survival and death is complex and may have diametrically opposed effects depending on the situation.…”

“…Immunohistochemistry (IHC) analysis was performed as reported above. 19 The prepared sections were incubated with anti-PARP, anti-p-Akt and anti-VIM antibodies overnight at 4 C, followed by biotin-conjugated secondary antibody. Images were obtained on a Leica DM4000B microscope (Leica, Wetzlar, Germany).…”

“…Standard western blot assays were conducted as described previously. 18,19 Antibodies against SQSTM1/p62 (D5E2), LC-3B (D11), phospho-Akt (Ser473), phospho-Akt (Thr308), total Akt, E-cadherin, N-cadherin and VIM were purchased from Cell Signaling Technology (Danvers, MA). Anti-β-actin (A5441) antibody was purchased from Sigma-Aldrich (St. Louis, MO).…”