Dig Dis Sci. 2021 Sep;66(9):3036-3044.doi: 10.1007/s10620-020-06640-5. Epub 2020 Oct 22.

Knockdown of Bcl-2-Associated Athanogene-3 Can Enhance the Efficacy of BGJ398 via Suppressing Migration and Inducing Apoptosis in Gastric Cancer

Ke Li  1 Xiang Deng  1 Guangjing Feng  2 Yi Chen  1 Affiliations

Abstract

Background: Gastric cancer (GC) is one of the most common malignancies of the digestive tract worldwide, and cancer cell resistance against anticancer drugs remains a major challenge for GC treatment. Nvp-BGJ398 (BGJ398) is considered as a common drug for cancer treatment; however, Bcl-2-associated athanogene-3 (BAG3) plays an important role in drug resistance.

Aims: To investigate the function of BAG3 on the sensitivity of GC cells to BGJ398.

Methods: The expression of BAG3 in GC cells and GC resistance cells was examined by qRT-PCR and western blot. The resistance to BGJ398 was detected by viability assay, and a half-maximal inhibitory concentration (IC50) was calculated. The cell migration and apoptosis were determined by wound-healing assay and flow cytometry assay.

Results: BAG3 was highly expressed in drug-resistant cells Fu97R and Snu16R. BAG3 was also associated with sensitivity of Snu16 cells to BGJ398, promoting migration but inhibiting apoptosis. However, knockdown of heat shock transcription factor 1 (HSF1) suppressed BAG3 expression and lowered the sensitivity to BGJ398 in Snu16R cells. Knockdown of BAG3 inhibited tumor growth and cell apoptosis but induced cell apoptosis and amplified the sensitivity to BGJ398 in Snu16R cells, followed by enhancing BGJ398-induced antitumor function in a Snu16R-derived xenograft mouse model.

Conclusion: The mechanism of resistance to BGJ398 in GC is mediated by BAG3/HSF1, and combined treatment with shBAG3 could improve the efficacy of BGJ398 in GC. Thus, BAG3-targeted therapy improves the antitumor efficacy of BGJ398, which might provide a novel therapeutic strategy for GC.

Keywords: Apoptosis; BAG3; Gastric cancer; NVP-BGJ398; Resistance.

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