Abstract
Pectolinarigenin (PEC), a natural flavonoid present in Cirsium chanroenicum and in some species of Citrus fruits, has various pharmacological benefits such as anti-inflammatory and anti-cancer activities. In the present study, we investigated the anti-cancer mechanism of PEC induced cell death caused by autophagy and apoptosis in AGS and MKN28 human gastric cancer cells. The PEC treatment significantly inhibited the AGS and MKN28 cell growth in a dose-dependent manner. Further, PEC significantly elevated sub-G1 phase in AGS cells and G2/M phase cell cycle arrest in both AGS and MKN28 cells. Apoptosis was confirmed by Annexin V and Hoechst 33342 fluorescent staining. Moreover, Immunoblotting results revealed that PEC treatment down-regulated the inhibitor of apoptosis protein (IAP) family protein XIAP that leads to the activation of caspase-3 thereby cleavage of PARP (poly-ADP-ribose polymerase) in both AGS and MKN28 cells in a dose-dependent manner. The autophagy-inducing effect was indicated by the increased formation of acidic vesicular organelles (AVOs) and increased protein levels of LC3-II conversion in both AGS and MKN28 cells. PEC shows the down regulation of PI3K/AKT/mTOR pathway which is a major regulator of autophagic and apoptotic cell death in cancer cells that leads to the down-regulation of p-4EBP1, p-p70S6K, and p-eIF4E in PEC treated cells when compared with the untreated cells. In conclusion, PEC treatment might have anti-cancer effect by down-regulation of PI3K/AKT/mTOR pathway leading to G2/M phase cell cycle arrest, autophagic and apoptotic cell death in human gastric cancer cells. Further studies of PEC treatment can support to develop as a potential alternative therapeutic agent for human gastric carcinoma.
Highlights
Gastric cancer remains a predominant public health confrontation and a ferocious cause of death worldwide
Up-regulation of AKT is involved in the conservation of X-linked Inhibitor of Apoptosis (XIAP) degradation by chemotherapeutic agents in malignant cells [11,12,13]. mTOR, a key negative regulator of autophagy, is a serine/threonine protein kinase that modulates cell growth, cell proliferation, and protein synthesis
Pectolinarigenin (PEC) Inhibits Gastric Cancer Cell Growth in a Dose-Dependent Manner cell viability was examined in gastric cancer cells AGS and MKN28 with MTT assay
Summary
Gastric cancer remains a predominant public health confrontation and a ferocious cause of death worldwide. Apoptosis is an evolutionary conserved and highly regulated cell death program that involves the suicide of cells in response to a number of stimuli, such as growth factor deprivation, antitumor drugs, and ionizing radiation, with the aim of preventing damage, stress, or the accumulation of non-functional cells in the tissue. Many studies have confirmed the PI3K/AKT/mTOR signaling pathway disorders in tumors, and in the biological regulation of gastric, liver, breast, colorectal and prostate cancer cells. PI3K/AKT activity is increased which activates mTOR complex via phosphorylation and decreases the feedback activation of p70S6k1/mTOR complex These changes lead to increased and uncontrolled mitochondrial processes, ribosome biogenesis and angiogenesis for increased protein synthesis, cell proliferation, cell growth, and autophagy [18,19,20].
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