IMB-6G, a novel N-substituted sophoridinic acid derivative, induces endoplasmic reticulum stress-mediated apoptosis via activation of IRE1α and PERK signaling

Abstract

Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which precede induction of apoptosis. Further study showed IMB-6G activated IRE1α and PERK pathways but did not stimulated ATF6 pathway in HCC cells. Moreover, silencing of IRE1α dramatically abrogated IMB-6G-induced pro-apoptotic ASK1-JNK signaling. Importantly, interruption of CHOP rendered HCC cells sensitive to IMB-6G-induced apoptosis via inactivation of Bim, PUMA and Bax. Thus, the IRE1α-ASK1 and PERK-CHOP pathways may be a novel molecular mechanism of IMB-6G-induced apoptosis. Collectively, our study demonstrates that IMB-6G induces ER stress-mediated apoptosis by activating IRE1α and PERK pathways. Our findings provide a rationale for the potential application of IMB-6G in HCC therapy.

IMB‑6G induces endoplasmic reticulum stress‑mediated apoptosis in human nasopharyngeal carcinoma cells

“…Therefore, there is an urgency to identify novel and efficient agents for the treatment of patients with advanced NPC. IMB-6G, a novel N-substituted sophoridinic acid derivative, has been demonstrated to have anti-tumor effect (13,14); however, little is known about its effect on NPC. In the present study, the effect of IMB-6G and any associated possible signaling pathways was investigated on human NPC C666-1 cells in vitro.…”

“…B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein-regulated Ca 2+ release from the ER, IRE1α-mediated tumor necrosis factor receptor-associated factor 2 activation and PERK/eIF2α-dependent induction of the proapoptotic transcriptional factor CHOP (C/EBP homologous protein) are all associated with ER stress-mediated apoptosis (23)(24)(25). A previous study reported that IMB-6G induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells by activating IRE1α and PERK signaling pathways (14). Therefore, it was investigated whether IRE1α and PERK signaling pathways were involved in ER stress-mediated apoptosis in human NPC C666-1 cells in the present study.…”

“…The NPC cell line C666-1 was obtained from the Chinese Academy of Sciences Cell Bank (Shanghai, China) and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (HyClone, Logan, UT, USA), 1% penicillin/streptomycin solution at 37˚C in an atmosphere containing 5% CO 2 . Cells were treated with various concentrations of IMB-6G (0, 1, 2 and 5 µM) for 24 h at 37˚C as described previously (14) prior to experiments described below.…”

“…As a novel N-substituted sophoridine acid derivative, IMB-6G has been indicated to have an anti-proliferation effect on several human tumor cells through inducing apoptosis and G 0 /G 1 cell cycle arrest (13). Zhang et al (14) reported that IMB-6G induces endoplasmic reticulum (ER) stress-mediated apoptosis through the activation of inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK) signaling pathways. Furthermore, IMB-6G also exhibits reasonable bio-availability and has been demonstrated to possess positive pharmacokinetic properties and exhibits good safety profile in vivo (13,15).…”

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

“…11 CCAATenhancer-binding protein homologous protein can inhibit the expression of antiapoptotic Bcl-2 family proteins and can activate proapoptotic BH3 family proteins: Bcl2-like protein 11, p53 upregulator modulator of apoptosis, and Bcl2-associated X protein. 12 In hypoxic tumors, CHOP activation of autophagy can serve to be a protective tolerance-mediating mechanism, promoting survival. 13 Protein kinase RNA-like endoplasmic reticulum kinase is able to activate Nrf2 phosphorylation in an attempt to maintain redox balance within the cell.…”