RETRACTED ARTICLE: Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway

Abstract

Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid isolated from the medicinal plant S. involucrata, which exhibits anti-neoplastic activity against several types of cancer. However, the mechanism underlying its anti-cancer activity against hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we investigated whether and how hispidulin-induced apoptosis of human HCC cells in vitro and in vivo. We showed that hispidulin (10, 20 μmol/L) dose-dependently inhibited cell growth and promoted apoptosis through mitochondrial apoptosis pathway in human HCC SMMC7721 cells and Huh7 cells. More importantly, we revealed that its pro-apoptotic effects depended on endoplasmic reticulum stress (ERS) and unfolded protein response (UPR), as pretreatment with salubrinal, a selective ERS inhibitor, or shRNA targeting a UPR protein CHOP effectively abrogated hispidulin-induced cell apoptosis. Furthermore, we showed that hispidulin-induced apoptosis was mediated by activation of AMPK/mTOR signaling pathway as pretreatment with Compound C, an AMPK inhibitor, or AMPK-targeting siRNA reversed the pro-apoptotic effect of hispidulin. In HCC xenograft nude mice, administration of hispidulin (25, 50 mg kg d, ip, for 27 days) dose-dependently suppressed the tumor growth, accompanied by inducing ERS and apoptosis in tumor tissue. Taken together, our results demonstrate that hispidulin induces ERS-mediated apoptosis in HCC cells via activating the AMPK/mTOR pathway. This study provides new insights into the anti-tumor activity of hispidulin in HCC.

Hispidulin exhibits potent anticancer activity in�vitro and in�vivo through activating ER stress in non‑small‑cell lung cancer cells

“…In the current study, hispidulin markedly inhibited the tumor growth at doses of 20 and 40 mg/kg. The mouse body weight was not significantly affected by hispidulin in HCC xenograft mouse models (15). Consistent with this finding, the current study found that the body weight of NCI-H460 xenograft mouse models changed slightly at both doses and was not significantly different compared with vehicle control.…”

“…Vascular endothelial growth factor-induced cell invasion, migration, and capillary-like structure formation were also inhibited by hispidulin (25). The effect of hispidulin on the liver system has also been reported (15). However, the molecular mechanisms of anticancer effect induced by hispidulin in NSCLC cells remain unclear.…”

“…Accumulated evidence has demonstrated that hispidulin has various effects, such as pro-oxidant, neuroprotective, anti-inflammatory, antiepileptic, antithrombotic, and antiosteoporotic activities (9)(10)(11)(12)(13). Furthermore, a number of in vivo and in vitro studies have shown that hispidulin has antitumor effects on diverse hematological and solid malignancies (14)(15)(16)(17). The anticancer activities of hispidulin in acute myeloid leukemia, colorectal cancer, renal cell carcinoma, gallbladder cancer and hepatocellular carcinoma have also been confirmed (16)(17)(18).…”

Retracted: Alpinumisoflavone Inhibits Tumor Growth and Metastasis in Papillary Thyroid Cancer via Upregulating miR‐141‐3p

“…In last decades, the antitumor effect of naturally occurring flavonoid compounds has been extensively studied, such as hispidulin (Gao et al, ; Liu et al, ; Han et al, ), curcumin (Sun et al, ), and quercetin (Tao et al, ). Additionally, a great deal of evidence has revealed that AIF possesses a broad spectrum of anticancer activities against various types of cancers.…”

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

“…In detail, hispidulin induced ER stress-mediated apoptosis in hepatocellular carcinoma cells by activating the 5 AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. Treatment of cells with AMPK siRNA or an inhibitor significantly abrogated the effects of hispidulin on CHOP expression and apoptotic-related protein expression, providing evidence that hispidulin triggers ER stress (ERS) by modulating AMPK signaling [48].…”