3,3'-Diindolylmethane induces gastric cancer cells death via STIM1 mediated store-operated calcium entry

Abstract

3,3'-Diindolylmethane (DIM), a natural phytochemicals isolated from cruciferous vegetables, has been reported to inhibit human gastric cancer cells proliferation and induce cells apoptosis as well as autophagy, but its mechanisms are still unclear. Store-operated calcium entry (SOCE) is a main Ca 2+ influx pathway in various of cancers, which is activated by the depletion of endoplasmic reticulum (ER) Ca 2+ store. Stromal interaction molecular 1 (STIM1) is the necessary component of SOCE. In this study, we focus on to examine the regulatory mechanism of SOCE on DIM-induced death in gastric cancer. After treating the human BGC-823 and SGC-7901 gastric cancer cells with DIM, cellular proliferation was determined by MTT, apoptosis and autophagy were detected by flow cytometry or Hoechst 33342 staining. The expression levels of related proteins were evaluated by Western blotting. Free cytosolilc Ca 2+ level was assessed by fluorescence monitoring under a laser scanning confocal microscope. The data have shown that DIM could significantly inhibit proliferation and induce apoptosis as well as autophagy in two gastric cancer cell lines. After DIM treatment, the STIM1-mediated SOCE was activated by upregulating STIM1 and decreasing ER Ca 2+ level. Knockdown STIM1 with siRNA or pharmacological inhibition of SOCE attenuated DIM induced apoptosis and autophagy by inhibiting p-AMPK mediated ER stress pathway. Our data highlighted that the potential of SOCE as a promising target for treating cancers. Developing effective and selective activators targeting STIM1-mediated SOCE pathway will facilitate better therapeutic sensitivity of phytochemicals acting on SOCE in gastric cancer. Moreover, more research should be performed to validate the efficacy of combination chemotherapy of anti-cancer drugs targeting SOCE for clinical application.

Anticancer applications of phytochemicals in gastric cancer: Effects and molecular mechanism

“…Kaempferol, p-Coumaric acid, Astragalin and Tiliroside influence abnormal glycosylation of GC cells, so as to exert the anticancer effect ( Radziejewska et al, 2022 ). DIM suppressed GC via mediated ferroptosis, store-operated calcium entry, gastric cancer-derived mesenchymal stem cells, endogenous hydrogen sulfide biosynthesis ( Ye et al, 2020 ; Ye et al, 2021b ; Shi et al, 2021 ; Ye et al, 2022 ). It is reported that phytochemicals showed anticancer properties against GC associated with tumor viral infections ( Liskova et al, 2021 ; Sudomova et al, 2021 ).…”

3,3′-Diindolylmethane induces ferroptosis by BAP1–IP3R axis in BGC-823 gastric cancer cells

“…One-way analysis of variance was used to calculate the significant differences among groups. A value of P < 0.05 was considered significant [18].…”

“…Our previous study has shown that DIM is known to induce apoptosis and autophagy via IP3R-mediated ER calcium store Ca 2+ release in gastric cancer [18]. However, the role of IP3R in DIM-induced ferroptosis has not been elucidated.…”

“…Forty micrograms of total protein were used for immunoblotting analysis, then incubated with primary antibodies against the following proteins at 4°C overnight. The membranes were incubated with the corresponding horseradish peroxidase-conjugated secondary IgG for 1 h [18].…”

3,3′-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

“…3,3-diindolylmethane (DIM) is a natural product found in cruciferous edible plants, such as cauliflower, cabbage, and broccoli. Previous studies have reported that DIM has several preventive effects, especially displaying anti-tumor, anti-inflammatory, antioxidant and free radical scavenging roles ( Luo et al, 2018 ; Ye et al, 2021 ). Recent studies have determined that DIM also protects against kidney, heart, and liver damage.…”