Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15

Abstract

We investigated the effects of isoalantolactone on cell growth inhibition and underlying cell death mechanisms in SKOV3 human ovarian cancer cells. The effects of isoalantolactone on cell proliferation and cell cycle were examined by EdU incorporation assay and DNA content assay. Western blotting was performed to determine the protein expression effects of isoalantolactone on cell cycle‑related proteins, autophagic regulators and PEA‑15. Autophagic vacuoles were observed by acridine orange staining. PEA‑15 knockdown by siRNA was used to confirm that PEA‑15 was involved in isoalantolactone‑induced autophagy of SKOV3 cells. Isoalantolactone inhibited the viability and proliferation of SKOV3 cells in a dose‑ and time‑dependent fashion. Isoalantolactone induced cell cycle arrest at G2/M phase and decreased the expression of cell cycle‑related proteins cyclin B1 and CDK1 in SKOV3 cells. Accordingly, isoalantolactone also induced SKOV3 cell autophagy via accumulation of autophagic vacuoles in the cytoplasm, increased Beclin1 protein expression, and increased LC3 cleavage. Furthermore, we observed that isoalantolactone‑induced autophagy was through increased PEA‑15 expression and the phosphorylation of ERK, whereas less change was observed to autophagy on SKOV3 cells through PEA‑15 knockdown by siRNA. Isoalantolactone‑induced autophagic cell death was further confirmed by pretreatment with the autophagy inhibitor 3‑methyladenine (3‑MA). In conclusion, isoalantolactone induced cell cycle arrest and autophagy and inhibited cell proliferation of SKOV3 cells via the upregulated PEA‑15 expression and the phosphorylation of ERK.

Ethyl acetate extract from Inula�helenium L. inhibits the proliferation of pancreatic cancer cells by regulating the STAT3/AKT pathway

“…As previously reported, sesquiterpene lactones are a class of chemical compounds responsible for the anti-cancer activity of IHL (17). Among those sesquiterpene lactones, alantolactone and isoalantolactone are the most extensively studied compounds obtained from the ethanol extracts of IHL (18,19). However, there remain other sesquiterpene lactones that may also exhibit anti-cancer activity but have yet to be intensively studied (20).…”

Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

“…IATL has been shown to induce autophagy in ovarian carcinoma cells ( Weng et al, 2016 ). Here, we examined whether IATL affects autophagy in CRC cells.…”

“…Isoalantolactone (IATL) is a sesquiterpene lactone naturally occurring in the roots of Inula helenium L. IATL has been reported to exert cytotoxic effects against a variety of cancer cells, including pancreatic cancer ( Zhang et al, 2021 ), esophageal cancer ( Lu et al, 2018 ; Wen et al, 2018 ), hepatocellular carcinoma ( Kim et al, 2021 ), prostate cancer ( Rasul et al, 2013 ; Chen et al, 2018 ; Huang et al, 2021 ) and glioblastoma ( Xing et al, 2019 ). The anticancer effects of IATL mainly involve the induction of apoptosis, cell cycle arrest and autophagy ( Weng et al, 2016 ; Chen et al, 2018 ; Lu et al, 2018 ). However, the anti-CRC effects and mechanisms of action of IATL remain elusive.…”

Stevia Genus: Phytochemistry and Biological Activities Update

“…This compound has many biological activities described, one of them being the cytotoxic activity. Isoalantolactone has been proven to inhibit proliferation by the induction of apoptosis, autophagy, causing G1 phase arrest, or the activation of reactive oxygen species in gynecologic cancer cells, breast cancer, leukemia, and lung squamous cancer [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. This compound induced apoptosis by targeting multiple cellular signaling pathways.…”