Inhibition of endogenous hydrogen sulfide biosynthesis enhances the anti-cancer effect of 3,3′-diindolylmethane in human gastric cancer cells

Abstract Background Compound C-2 is a derivative of natural product Jaspine B and possesses anti-cancer activity against bladder cancer cells. However, little is known about its anti-cancer activity against gastric cancer. In this research, mechanism underlying anti-cancer effect of C-2 in gastric cancer cells was well investigated. Methods Anti-cancer activities of C-2 were determined by MTT, western blotting and flow cytometry. A serial of specific inhibitors, immunoprecipitation, siRNA and immunofluorescence were utilized to explore signaling pathways affected by C-2. Results C-2 induces apoptosis in gastric cancer cells through the internal mitochondrial pathway, and triggers autophagy in gastric cancer cells through JNK/ERK pathway. Phosphorylated JNK/ERK further activates Beclin1 via disturbing Beclin-1/Bcl-xL or Beclin-1/Bcl-2 complexes, leading to autophagy and up-regulated p62. Next, p62 competitively binds keap1 to release Nrf2, thus promoting translocation of Nrf2 from cytoplasm to nucleus and triggering expression of Nrf2 target genes. Pharmacological inhibition or knockdown of key proteins in autophagy attenuates C-2 induced cell apoptosis, indicating that autophagy antagonizes cell apoptosis induced by C-2. Conclusion C-2 possesses anti-tumor activity against gastric cancer cells, while C-2 triggered-autophagy antagonizes cell arrest and apoptosis induced by C-2 by upregulating Nrf2 in nucleus.

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An Anticancer Role of Hydrogen Sulfide in Human Gastric Cancer Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/636410 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Li Zhang ◽

Qi Qi ◽

Jianqiang Yang ◽

Dongsheng Sun ◽

Chunfeng Li ◽

...

Keyword(s):

Gastric Cancer ◽

Hydrogen Sulfide ◽

Cancer Cells ◽

Mammalian Cells ◽

Migration And Invasion ◽

Human Gastric Cancer ◽

Gastric Cancer Cells ◽

Induced Apoptosis ◽

Related Proteins

Hydrogen sulfide (H2S) can be synthesized in mammalian cells by cystathionineγ-lyase (CSE) and/or cystathionineβ-synthase (CBS). Both CSE and CBS are expressed in rat gastric tissues but their role in human gastric neoplasia has been unclear. The aims of the present study were to detect CSE and CBS proteins in human gastric cancer and determine the effect of exogenous NaHS on the proliferation of gastric cancer cells. We found that both CSE and CBS proteins were expressed in human gastric cancer cells and upregulated in human gastric carcinoma mucosa compared with those in noncancerous gastric samples. NaHS induced apoptosis of gastric cancer cells by regulating apoptosis related proteins. Also, NaHS inhibited cancer cell migration and invasion. An antigastric cancer role of H2S is thus indicated.

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Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.613458 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanne-Line Rabben ◽

Yosuke Kodama ◽

Masahiko Nakamura ◽

Atle Magnar Bones ◽

Timothy Cragin Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Genetically Engineered ◽

Human Gastric Cancer ◽

M Cell ◽

Gastric Cancer Cells ◽

Combination Strategy ◽

Genetically Engineered Mouse Model ◽

Anti Cancer

Naturally occurring isothiocyanates (ITCs) from edible vegetables have shown potential as chemopreventive agents against several types of cancer. The aims of the present study were to study the potential of ITCs in chemoprevention and in potentiating the efficacy of cytotoxic drugs in gastric cancer treatment. The chemoprevention was studied in chemically induced mouse model of gastric cancer, namely N-methyl-N-nitrosourea (MNU) in drinking water, and in a genetically engineered mouse model of gastric cancer (the so-called INS-GAS mice). The pharmacological effects of ITCs with or without cisplatin were studied in human gastric cell lines MKN45, AGS, MKN74 and KATO-III, which were derived from either intestinal or diffused types of gastric carcinoma. The results showed that dietary phenethyl isothiocyanate (PEITC) reduced the tumor size when PEITC was given simultaneously with MNU, but neither when administrated after MNU nor in INS-GAS mice. Treatments of gastric cancer cells with ITCs resulted in a time- and concentration-dependent inhibition on cell proliferation. Pretreatment of gastric cancer cells with ITCs enhanced the inhibitory effects of cisplatin (but not 5-fluorouracil) in time- and concentration-dependent manners. Treatments of gastric cancer cells with PEITC plus cisplatin simultaneously at different concentrations of either PEITC or cisplatin exhibited neither additive nor synergetic inhibitory effect. Furthermore, PEITC depleted glutathione and induced G2/M cell cycle arrest in gastric cancer cells. In conclusion, the results of the present study showed that PEITC displayed anti-cancer effects, particularly when given before the tumor initiation, suggesting a chemopreventive effect in gastric cancer, and that pretreatment of PEITC potentiated the anti-cancer effects of cisplatin, possibly by reducing the intracellular pool of glutathione, suggesting a possible combination strategy of chemotherapy with pretreatment with PEITC.

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Diosgenin inhibits the proliferation of gastric cancer cells via inducing mesoderm posterior 1 down-regulation-mediated alternative reading frame expression

Human & Experimental Toxicology ◽

10.1177/09603271211053292 ◽

2021 ◽

pp. 096032712110532

Author(s):

Lin Gu ◽

Hailun Zheng ◽

Rui Zhao ◽

Xiaojing Zhang ◽

Qizhi Wang

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Human Gastric Cancer ◽

Gastric Cancer Cells ◽

Reading Frame ◽

Anti Cancer ◽

Cancer Tissues ◽

Alternative Reading

Introduction Whether and how mesoderm posterior 1 (MESP1) plays a role in the proliferation of gastric cancer cells remain unclear. Methods The expression of MESP1 was compared in 48 human gastric cancer tissues and adjacent normal tissues. Knockdown of MESP1 was performed to investigate the role of MESP1 in the proliferation and apoptosis of BGC-823 and MGC-803 gastric cancer cells. Knockdown of alternative reading frame (ARF) was performed to study the role of ARF in the inhibitory effect of MESP1 knockdown on cell proliferation in gastric cancer cells. Mouse subcutaneous xenograft tumor model bearing BGC-823 cells was used to investigate the role of MESP1 in the growth of gastric tumor in vivo. The effect of seven active ingredients from T. terrestris on MESP1 expression was tested. The anti-cancer effect of diosgenin was confirmed in gastric cancer cells. MESP1 dependence of the anti-cancer effect of diosgenin was confirmed by MESP1 knockdown. Results MESP1 was highly expressed in human gastric cancer tissues ( p < 0.05). MESP1 knockdown induced apoptosis and up-regulated the expression of ARF in gastric cancer cells ( p < 0.05). Knockdown of ARF attenuated the anti-cancer effect of MESP1 knockdown ( p < 0.05). In addition, MESP1 knockdown also suppressed tumor growth in vivo ( p < 0.05). Diosgenin inhibits both mRNA and protein expression of MESP1 ( p < 0.05). MESP1 knockdown attenuated the anti-cancer effect of diosgenin ( p < 0.05). Conclusions MESP1 promotes the proliferation of gastric cancer cells via inhibiting ARF expression. Diosgenin exerts anti-cancer effect through inhibiting MESP1 expression in gastric cancer cells.

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