Propranolol suppresses gastric cancer cell growth by regulating proliferation and apoptosis
Propranolol suppresses gastric cancer cell growth by regulating proliferation and apoptosis
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DOI：
10.1007/s10120-021-01184-7
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发表时间：
2021-03-29
期刊：
影响因子：
7.4
通讯作者：
Doki, Yuichiro
中科院分区：
文献类型：
--
作者：
Koh, Masahiro;Takahashi, Tsuyoshi;Doki, Yuichiro
背景尽管胃癌治疗有所改善，但晚期胃癌的死亡率仍然很高。压力激活β-肾上腺素受体已被证明会加速多种癌症的进展。因此，越来越多的证据表明，阻断β-肾上腺素信号传导可以抑制肿瘤生长。然而，针对多种信号通路的β受体阻滞剂对胃癌的作用仍有待阐明。本研究旨在探讨普萘洛尔（一种非选择性β受体阻滞剂）对胃癌的抗肿瘤作用。方法 我们探讨普萘洛尔对 MKN45 和 NUGC3 胃癌细胞系的影响。使用多种测定（例如细胞增殖、细胞周期、细胞凋亡和伤口愈合）和异种移植小鼠模型检查了其功效及其发挥抗肿瘤作用的机制。结果我们发现普萘洛尔抑制两种细胞系中的肿瘤生长并诱导 G1 期细胞周期停滞和凋亡。普萘洛尔还降低磷酸化 CREB-ATF 和 MEK-ERK 通路的表达；抑制基质金属蛋白酶2、9和血管内皮生长因子的表达；并抑制胃癌细胞的迁移。在异种移植小鼠模型中，普萘洛尔治疗显着抑制肿瘤生长，免疫组织化学显示普萘洛尔可抑制增殖并诱导细胞凋亡。结论普萘洛尔通过诱导G1期细胞周期阻滞和细胞凋亡抑制胃癌细胞增殖。这些发现表明普萘洛尔可能有机会成为治疗胃癌的新药。
Background Despite improvements in gastric cancer treatment, the mortality associated with advanced gastric cancer is still high. The activation of beta-adrenergic receptors by stress has been shown to accelerate the progression of several cancers. Accordingly, increasing evidence suggests that the blockade of beta-adrenergic signaling can inhibit tumor growth. However, the effect of beta-blockers, which target several signaling pathways, on gastric cancer remains to be elucidated. This study aimed to investigate the anti-tumor effects of propranolol, a non-selective beta-blocker, on gastric cancer. Methods We explored the effect of propranolol on the MKN45 and NUGC3 gastric cancer cell lines. Its efficacy and the mechanism by which it exerts anti-tumor effects were examined using several assays (e.g., cell proliferation, cell cycle, apoptosis, and wound healing) and a xenograft mouse model. Results We found that propranolol inhibited tumor growth and induced G1-phase cell cycle arrest and apoptosis in both cell lines. Propranolol also decreased the expression of phosphorylated CREB-ATF and MEK-ERK pathways; suppressed the expression of matrix metalloproteinase-2, 9 and vascular endothelial growth factor; and inhibited gastric cancer cell migration. In the xenograft mouse model, propranolol treatment significantly inhibited tumor growth, and immunohistochemistry revealed that propranolol led to the suppression of proliferation and induction of apoptosis. Conclusions Propranolol inhibits the proliferation of gastric cancer cells by inducing G1-phase cell cycle arrest and apoptosis. These findings indicate that propranolol might have an opportunity as a new drug for gastric cancer.