Babao dan promotes apoptosis of cisplatin (DDP)-resistant gastric cancer cell line SGC-7901/DDP by inducing autophagy through PI3K/AKT/mTOR pathway modulation

Abstract Background: Multidrug resistance (MDR) is a critical reason of cancer chemotherapy failure. Babao dan (BBD) is a classical and famous traditional Chinese patent medicine, which has been reported to has anti-gastric cancer activity. However, the roles and molecular mechanisms of the reversal of MDR of gastric cancer by BBD have not been well described until now. Methods: SGC-7901 and SGC-7901/DDP cells were used in this study, and drug resistance and evaluation of the reversal effect of BBD was determined using MTT assays in SGC7901/DDP cells. Doxorubicin (DOX) and Rhodamin123 (Rho123) staining was performed to assess BBD effects on drug accumulation and efflux of drug-resistant gastric cancer cells. Cell apoptosis was directly assessed using DAPI staining. Apoptotic and dead cells were detected by flow cytometry after staining with Annexin V-FITC and propidium iodide (PI). Cyto-ID assays were performed to examine cellular autophagy. Changes in cell protein expression of ABCB1, ABCC1, ABCG2, Bax, Bcl-2, caspase-3, cleaved-caspase-3, LC3, p62, Beclin1 and the PI3K/AKT/mTOR pathway were detected by Western blot. Inhibition of autophagy with 3-MA, chloroquine (CQ) and PI3K antagonist (LY294002) or agonist (740Y-P) , uncovered a role for the potentially downregulated signaling pathway, PI3K/AKT/mTOR.Results: The SGC7901/DDP cell line exhibited multi-drug resistance to DDP, DOX and 5-fluorouracil (5-FU) and the drug resistant index (RI) of DDP, DOX and 5-FU were 1.86, 1.50 and 47.70, respectively. BBD reversed the MDR of SGC7901/DDP cells by increasingDOX accumulation, reducing Rh123 efflux and down-regulating the expression of ABCB1, ABCC1, ABCG2. Furthermore, BBD induced apoptosis in SGC7901/DDP cells through regulating caspase-3, cleaved-caspase-3, Bax and Bcl-2. Moreover, BBD induced autophagy in DDP-resistant gastric cancer cells via regulating p62, LC3 and Beclin1. Pathway analyses suggested BBD may inhibit PI3K/AKT/mTOR pathway activity and subsequent autophagy induction. Conclusions: BBD may reverse the MDR of gastric cancer cells, and promote autophagic death via inactivation of the PI3K/AKT/mTOR signaling pathway.

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Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway

Cancer Gene Therapy ◽

10.1038/cgt.2014.59 ◽

2014 ◽

Vol 21 (12) ◽

pp. 526-531 ◽

Cited By ~ 5

Author(s):

B Tan ◽

Y Li ◽

Q Zhao ◽

L Fan ◽

Y Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Signaling Pathway ◽

Gastric Cancer Cells ◽

Jnk Signaling ◽

Jnk Signaling Pathway

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TSPAN9 suppresses the chemosensitivity of gastric cancer to 5-fluorouracil by promoting autophagy

Cancer Cell International ◽

10.1186/s12935-019-1089-2 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 4

Author(s):

Yaoyue Qi ◽

Weiwei Qi ◽

Shihai Liu ◽

Libin Sun ◽

Aiping Ding ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Transmembrane Protein ◽

Pi3k Pathway ◽

Drug Resistant ◽

Gastric Cancer Cells ◽

Autophagy Pathway ◽

Resistant Cells

Abstract Background The issue of drug resistance in gastric cancer has attracted global attention. TSPAN9, a 4-transmembrane protein that plays an important role in tumor progression and signal transduction, has been found to be closely related to tumor invasion, metastasis, and autophagy. Methods Immunoblotting was used to evaluate TSPAN9 expression in parental and drug-resistant gastric cancer cells. Functional assays, such as the CCK-8 assay, were used to detect the proliferation of gastric cancer cells and the response of TSPAN9 to 5-fluorouracil (5-FU). Western blotting was used to analyze the expression of constituents of the PI3K/AKT/mTOR-mediated autophagy pathway induced by TSPAN9. Coimmunoprecipitation was performed to assess the specific mechanism by which TSPAN9 affects the PI3K pathway. Results We demonstrated that TSPAN9 is overexpressed in 5-FU-resistant cells compared to parental cells. 5-FU-mediated inhibition of cell proliferation can be significantly restored by increasing TSPAN9 expression, and inhibiting this expression in drug-resistant cells can restore the sensitivity of the cells to 5-FU. In addition, TSPAN9 also significantly promoted autophagy in gastric cancer cells in vitro. Further studies indicated that TSPAN9 downregulates the expression of PI3K and proteins associated with PI3K-mediated autophagy. In addition, TSPAN9 interacts with PI3K and inhibits its catalytic activity. Conclusion The current study reveals the important role of TSPAN9 in drug resistance to 5-FU in gastric cancer. It also provides a new target to clinically address drug-resistant gastric cancer and will contribute to the treatment strategy of this disease.

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Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

Molecular Medicine Reports ◽

10.3892/mmr.2016.5426 ◽

2016 ◽

Vol 14 (2) ◽

pp. 1817-1822 ◽

Cited By ~ 9

Author(s):

Hongyan Zhao ◽

Dali Zhao ◽

Huilin Jin ◽

Hongwei Li ◽

Xiaoying Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Gastric Cancer Cells ◽

Acquired Drug Resistance

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Procyanidin B2 induces apoptosis and autophagy in gastric cancer cells by inhibiting Akt/mTOR signaling pathway

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03225-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yuqin Li ◽

Xiaolan Lu ◽

Peiying Tian ◽

Kai Wang ◽

Jianping Shi

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Caspase 3 ◽

Mtor Signaling ◽

Therapeutic Drug ◽

Tunel Staining ◽

Dependent Manner ◽

Mtor Signaling Pathway ◽

Gastric Cancer Cells

Abstract Background Procyanidin B2 (PB2), a unique component of the grape seed and other medicinal plants. PB2 has shown wide anticancer activity in various human cancer cells. However, it remains unclear about the biological effects and associated mechanisms of PB2 on gastric cancer cells. Methods Cell proliferation was measured by CCK8 assay, and cellular lactate dehydrogenase (LDH) release was measured in the culture medium. Cellular apoptosis was observed via TUNEL staining assay and measured by caspase-3 and -9 activities. Autophagy was observed by LC3 staining. Western blot analysis was performed to verify autophagy-associated proteins (Beclin1 and Atg5) and Akt-mTOR pathway. Results PB2 reduced the viability of BGC-823 and SGC-7901 cells in a concentration-dependent manner. Furthermore, PB2 induced increased apoptosis rate of gastric cancer cells and enhanced caspase-3 and -9 activities. Simultaneously, PB2 triggered autophagy in gastric cancer cells, with enhanced LC3 staining and increased expression of Beclin1 and Atg5, while the inhibition of autophagy by 3-MA reversed the PB2-induced suppression on cell viability. In addition, PB2 significantly decreased p-Akt and p-mTOR protein expression of gastric cancer cells. Conclusion PB2 exerts anti-proliferative and apoptotic effects and induces autophagy by modulating Akt/mTOR signaling pathway. PB2 may be developed as a potential therapeutic drug for gastric cancer.

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miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer

Open Medicine ◽

10.1515/med-2021-0313 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1206-1214

Author(s):

Rui Su ◽

Enhong Zhao ◽

Jun Zhang

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Caspase 3 ◽

Mtor Signaling ◽

Migration And Invasion ◽

Human Gastric Cancer ◽

Mtor Signaling Pathway ◽

Gastric Cancer Cells ◽

Ags Cells

Abstract MicroRNAs (miRNAs) operate as tumor suppressor or carcinogen to regulate cell proliferation, metastasis, invasion, differentiation, apoptosis, and metabolic process. In the present research, we investigated the effect and mechanism of miR-496 in human gastric cancer cells. miR-496 was downregulated in two gastric cancer cell lines, AGS and MKN45, compared with normal gastric epithelial cell line GES-1. miR-496 mimics inhibited the proliferation of AGS cells after the transfection for 48 and 72 h. The migration and invasion of AGS cells were also inhibited by the transfection of miR-496 mimics. miR-496 mimics induced the apoptosis through upregulating the levels of Bax and Active Caspase 3 and downregulating the levels of Bcl-2 and Total Caspase 3. Bioinformatics analysis showed that there was a binding site between miR-496 and Lyn kinase (LYN). miR-496 mimics could inhibit the expression of LYN in AGS cells. LYN overexpression blocked the inhibition of tumor cell growth, as well as the inhibition of AKT/mTOR signaling pathway induced by miR-496. In conclusion, miR-496 inhibited the proliferation through the AKT/mTOR signaling pathway via targeting LYN in gastric cancer cells. Our research provides a new potential target for clinical diagnosis and targeted treatment for gastric cancer.

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Silencing of the ARK5 gene reverses the drug resistance of multidrug-resistant SGC7901/DDP gastric cancer cells

PeerJ ◽

10.7717/peerj.9560 ◽

2020 ◽

Vol 8 ◽

pp. e9560

Author(s):

Hongtao Wan ◽

Xiaowei Liu ◽

Yanglin Chen ◽

Ren Tang ◽

Bo Yi ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Multidrug Resistance ◽

Cancer Cells ◽

Cell Line ◽

Cell Apoptosis ◽

Colony Formation ◽

Chemotherapeutic Drugs ◽

Gastric Cancer Cells

For several years, the multidrug resistance (MDR) of gastric cancer cells has been a thorny issue worldwide regarding the chemotherapy process and needs to be solved. Here, we report that the ARK5 gene could promote the multidrug resistance of gastric cancer cells in vitro and in vivo. In this study, LV-ARK5-RNAi lentivirus was used to transfect the parental cell line SGC7901 and MDR cell line SGC7901/DDP to construct a stable model of ARK5 interference. Subsequently, the cells were treated with four chemotherapeutic drugs, cisplatin (DDP), adriamycin (ADR), 5-fluorouracil (5-FU) and docetaxel (DR) and were subjected to the CCK8, colony formation, adriamycin accumulation and retention, cell apoptosis and other assays. The study found that, in vitro, the expression of ARK5 in MDR gastric cancer cells was significantly higher than that in parental cells. Additionally, when treated with different chemotherapeutic drugs, compared with parental cells, MDR cells also had a higher cell survival rate, higher colony formation number, higher drug pump rate, and lower cell apoptosis rate. Additionally, in xenograft mouse models, MDR cells with high ARK5 expression showed higher resistance to chemotherapeutic drugs than parental cells. Overall, this study revealed that silencing the ARK5 gene can effectively reverse the drug resistance of MDR gastric cancer cells to chemotherapeutic drugs, providing insights into the mechanism of this process related to its inhibition of the active pump-out ability of MDR cells.

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