Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Qizhi Road, Jiangbei District, Chongqing, 400000, China.
Dig Dis Sci. 2021 Sep;66(9):3036-3044. doi: 10.1007/s10620-020-06640-5. Epub 2020 Oct 22.
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.
To investigate the function of BAG3 on the sensitivity of GC cells to BGJ398.
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 (IC) was calculated. The cell migration and apoptosis were determined by wound-healing assay and flow cytometry assay.
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.
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.
胃癌（GC）是全球最常见的消化道恶性肿瘤之一，癌细胞对抗癌药物的耐药性仍是 GC 治疗的主要挑战。Nvp-BGJ398（BGJ398）被认为是一种常见的癌症治疗药物；然而，Bcl-2 相关抗凋亡基因 3（BAG3）在耐药性中发挥着重要作用。
探讨 BAG3 对 GC 细胞对 BGJ398 敏感性的影响。
通过 qRT-PCR 和 Western blot 检测 GC 细胞和 GC 耐药细胞中 BAG3 的表达。通过细胞活力测定检测 BGJ398 的耐药性，并计算半最大抑制浓度（IC）。通过划痕愈合试验和流式细胞术检测细胞迁移和凋亡。
BAG3 在耐药细胞 Fu97R 和 Snu16R 中高表达。BAG3 与 Snu16 细胞对 BGJ398 的敏感性相关，促进迁移但抑制凋亡。然而，热休克转录因子 1（HSF1）的敲低抑制了 BAG3 的表达，并降低了 Snu16R 细胞对 BGJ398 的敏感性。BAG3 的敲低抑制了肿瘤生长和细胞凋亡，但诱导了 Snu16R 细胞的细胞凋亡，并增强了 Snu16R 细胞对 BGJ398 的敏感性，随后在 Snu16R 衍生的异种移植小鼠模型中增强了 BGJ398 的抗肿瘤作用。
GC 对 BGJ398 的耐药机制是由 BAG3/HSF1 介导的，与 shBAG3 联合治疗可提高 GC 中 BGJ398 的疗效。因此，BAG3 靶向治疗可提高 BGJ398 的抗肿瘤疗效，为 GC 提供一种新的治疗策略。
