Zhang Xun, Yao Zhong, Xue Zhiyi, Wang Shuai, Liu Xuemeng, Hu Yaotian, Zhang Yan, Wang Jian, Li Xingang, Chen Anjing
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
Shandong Key Laboratory of Brain Function Remodeling and Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
Front Pharmacol. 2022 May 17;13:855626. doi: 10.3389/fphar.2022.855626. eCollection 2022.
Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172. Subsequently, we demonstrated that RB-induced G2/M phase arrest occurred through downregulation of CDC25C and upregulation of p21, which was caused by activation of the MAPK/ERK pathway, and that RB inhibited GBM invasion by elevating intercellular Ca to suppress the Src/FAK/Paxillin focal adhesion pathway. Intriguingly, we confirmed that upon RB binding to ATP1A1, Na-K-ATPase was activated as a receptor and then triggered the intracellular MAPK/ERK pathway and Ca-mediated Src/FAK/Paxillin focal adhesion pathway, which led to G2/M phase arrest and inhibited the invasion of GBM cells. Taken together, our findings reveal the antitumor mechanism of RB by targeting the ATP1A1 signaling cascade and two key signaling pathways and highlight the potential of RB as a new class of promising anticancer agents.
华蟾酥毒基（RB）是中药蟾酥中的主要活性成分，其在癌症治疗中的功效已受到广泛关注。然而，RB对胶质母细胞瘤（GBM）的抗癌作用及潜在机制仍不清楚。在此，我们发现RB可诱导原发性GBM细胞系P3#GBM以及两种GBM细胞系U251和A172发生G2/M期阻滞并抑制其侵袭。随后，我们证明RB诱导的G2/M期阻滞是通过下调细胞周期蛋白磷酸酶25C（CDC25C）和上调p21实现的，这是由丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路激活所导致的，并且RB通过提高细胞内钙离子浓度以抑制Src/黏着斑激酶（FAK）/桩蛋白（Paxillin）黏着斑通路来抑制GBM侵袭。有趣的是，我们证实RB与钠钾ATP酶α1亚基（ATP1A1）结合后，钠钾ATP酶作为受体被激活，进而触发细胞内MAPK/ERK通路以及钙离子介导的Src/FAK/Paxillin黏着斑通路，导致G2/M期阻滞并抑制GBM细胞的侵袭。综上所述，我们的研究结果揭示了RB通过靶向ATP1A1信号级联反应和两条关键信号通路的抗肿瘤机制，并突出了RB作为一类新型有前景的抗癌药物的潜力。
