Baicalein facilitates gastric cancer cell apoptosis by triggering endoplasmic reticulum stress via repression of the PI3K/AKT pathway

Abstract

Objective Gastric cancer (GC) remains a prevailing threat to life. Baicalein exhibits anti-cancer properties. This study estimated the mechanism of baicalein in GC cell apoptosis by mediating endoplasmic reticulum stress (ERS) through the PI3K/AKT pathway. Methods After treatment with different concentrations of baicalein, GC cell (HGC-27 and AGS) viability was detected by MTT assay. AGS cells more sensitive to baicalein treatment were selected as study subjects. The IC50 of baicalein on AGS cells was determined. Colony formation, cell cycle, and apoptosis were detected using crystal violet staining and flow cytometry. Levels of ERS-related and BTG3/PI3K/AKT pathway-related proteins were determined by Western blot. Intracellular Ca2+ level was measured using Fluo-3 AM fluorescence working solution. GC mouse models were established by subcutaneously injecting AGS cells into the right rib and were intragastrically administrated with baicalein. Tumor volume and weight were recorded. Expression of Ki67 in tumor tissues and positive expression of apoptotic cells were detected by immunohistochemistry and TUNEL staining. Results Baicalein inhibited cell proliferation and induced G0/G1 arrest and apoptosis by regulating the cell cycle, and triggered ERS in GC cells. Baicalein impeded the PI3K/AKT pathway by activating BTG3, thereby triggering ERS and inducing apoptosis. BTG3 inhibition reversed baicalein-induced apoptosis and ERS. Baicalein regulated GC cells in a concentration-dependent manner. Moreover, in xenograft mice, baicalein prevented tumor growth, decreased Ki67-positive cells, activated BTG3, and inhibited the PI3K/AKT pathway, thus activating ERS and increasing apoptotic cells. Conclusion Baicalein facilitates GC cell apoptosis by triggering ERS via repression of the PI3K/AKT pathway.

Network pharmacology, bioinformatics, and experimental validation to identify the role of Hedyotis diffusa willd against gastric cancer through the activation of the endoplasmic reticulum stress

“…By controlling the IRE1 pathway, according to Qian Gu et al Wogonoside increases apoptosis and ER stress in human gastric cancer cells [ 38 ]. By inducing ER stress, baicalein aids in the death of GC cells [ 39 ]. Asiaticoside accelerated ER stress and slowed the spread of GC [ 40 ].…”

The dual effect of endoplasmic reticulum stress in digestive system tumors and intervention of Chinese botanical drug extracts: a review

“…Baicalein, a flavonoid extracted from the root of the botanical drug Scutellaria baicalensis Georgi or Oroxylum indicum (L.) Vent., protects cells and fights against a variety of tumors ( Gan YC et al, 2023 ). Shen J et al (2023) found that baicalein (30, 60, 120 μM for 48 h) dose-dependently upregulated the expression of GRP78 and CHOP and blocked the PI3K/AKT pathway to trigger the ERS, blocking the cell cycle at G0/G1 phase and inhibited the proliferation of GC HGC-27 and AGS cells. The above effects were reversed with the addition of ERS inhibitor 4-PBA.…”

Flavonoids and Gastric Cancer Therapy: From Signaling Pathway to Therapeutic Significance

“… 128 , 129 Baicalein ( Figure 2 , 6) inhibited the PI3K/AKT pathway by activating BTG3, resulting in endoplasmic reticulum stress (ERS) and apoptosis. 52 Myricetin ( Figure 3 , 30), found in various natural plants including bayberry, induced apoptosis by inhibiting the PI3K/Akt/mTOR pathway, thereby reducing the expression of related proteins and affecting the viability of AGS cells. 98 Similarly, pectolinarigenin ( Figure 3 , 32), present in Cirsium chanroenicum , led to autophagy and apoptosis in AGS and MKN-28 cells by downregulating the PI3K/AKT/mTOR pathway.…”