Anticancer Action of Psilostachyin-A in 5-Fluorouracil-Resistant Human Liver Carcinoma are Mediated Through Autophagy Induction, G2/M Phase Cell Cycle Arrest and Inhibiting Extracellular-Signal-Regulated Kinase/Mitogen Activated Protein Kinase (ERK/MAPK) Signaling Pathway

Abstract

BackgroundLiver cancer is one of the most common malignancies around the world and one of the major causes of cancer related mortality. The objective of this study was to evaluate the anticancer effect of the natural compound psilostachyin-A on 5-fluorouracil-resistant human liver carcinoma cells and its effects on autophagy, cell cycle, caspase activation, and the ERK/MAPK signaling pathway.Material/MethodsCell Counting Kit 8 (CCK-8) assay was used to evaluate the effects on HepG2 cell viability at different doses of psilostachyin-A. Cell cycle analysis was performed using flow cytometry, and Transwell assay was used to check effects on cell invasion. Transmission electron microscopic studies were done to evaluate autophagy induced by psilostachyin-A, and the western blot method was carried out to evaluate the effects on autophagy and the ERK/MAPK signaling pathway.ResultsCCK-8 assay revealed that the psilostachyin-A reduced the cell viability of HepG2 cancer cells in a dose dependent manner. Psilostachyin-A also reduced the colony forming potential of HepG2 cells, concentration dependently. The IC50 of psilostachyin was found to be 25 μM. The anticancer effects of psilostachyin-A were due to the induction of autophagy which was accompanied by enhancement of LC3B II expression. Psilostachyin also caused cell cycle arrest by enhancing the accumulation of HepG2 cells in the G2/M phase. Transwell assay showed that psilostachyin-A suppressed the invasion of HepG2 cells. The results also showed that psilostachyin-A could block the ERK/MAPK pathway, indicative of the cytotoxic effects of psilostachyin-A on liver cancer.ConclusionsThese preliminary observations suggested that psilostachyin-A might prove beneficial in the treatment of liver cancer.

CDCA8 as an independent predictor for a poor prognosis in liver cancer

“…Liu et al study showed that targeting the MAPK pathway has additive and synergistic effects when with other pathways important for liver cancer cell proliferation, such as the mammalian target of rapamycin (mTOR) and Wnt/β-catenin pathways [ 21 ]. The natural compound psilostachyin-A exerts its cytotoxic effects on liver cancer by blocking the ERK/MAPK pathway [ 22 ]. In addition, overexpression and aberrant signaling of the ErbB family of receptors have been implicated in liver cancer, but the mechanisms underlying ErbB overexpression are unclear [ 23 ].…”

Lemur tyrosine kinase-3 (LMTK3) induces chemoresistance to cetuximab in colorectal cancer via the ERK/MAPK pathway

“…Previous reports revealed that ERK/MAPK actively participated in the development of chemoresistance to multiple drugs during chemotherapy for human cancers [24][25][26]. Besides, Raghav et al elucidated the ERK/MAPK pathway activated by HGF/MET axis could animate oncogenic signaling in CTX-resistant tumors to further aggravate chemoresistance [27], indicating that ERK/MAPK signaling contributed to CTX resistance in tumors.…”