Intercellular contractile force attenuates chemosensitivity through Notch-MVP-mediated nuclear drug export

IF 9.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Pengyu Du, Kai Tang, Xi Chen, Ying Xin, Bin Hu, Jianfeng Meng, Guanshuo Hu, Cunyu Zhang, Keming Li, Youhua Tan
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引用次数: 0

Abstract

Resistance to chemotherapeutics is one major challenge to clinical effectiveness of cancer treatment and is primarily interpreted by various biochemical mechanisms. This study establishes an inverse correlation between tumor cell contractility and chemosensitivity. In both clinical biopsies and cancer cell lines, high/low actomyosin-mediated contractile force attenuates/enhances the vulnerability to chemotherapy, which depends on intercellular force propagation. Cell–cell interaction force activates the mechanosensitive Notch signaling that upregulates the downstream effector major vault protein, which facilitates the export of chemotherapy drugs from nuclei, leading to the reduction of chemosensitivity. Cellular contractility promotes the tolerance of tumor xenografts to chemotherapy and sustains tumor growth in vivo, which can be reversed by the inhibition of contractile force, Notch signaling, or major vault protein. Further, the actomyosin-Notch signaling is associated with drug resistance and cancer recurrence of patients. These findings unveil a regulatory role of intercellular force in chemosensitivity, which could be harnessed as a promising target for cancer mechanotherapeutics.
细胞间收缩力通过notch - mvp介导的核药物输出减弱化学敏感性
化疗耐药是癌症治疗临床有效性的主要挑战之一,主要由各种生化机制来解释。本研究建立了肿瘤细胞收缩性与化疗敏感性之间的负相关关系。在临床活检和癌细胞系中,高/低肌动球蛋白介导的收缩力减弱/增强对化疗的易感性,这取决于细胞间力的传播。细胞-细胞相互作用力激活机械敏感的Notch信号,上调下游效应物主拱顶蛋白,促进化疗药物从细胞核输出,导致化疗敏感性降低。细胞收缩性促进肿瘤异种移植物对化疗的耐受性,并维持肿瘤在体内的生长,这可以通过抑制收缩力、Notch信号或主要拱顶蛋白来逆转。此外,肌动球蛋白notch信号通路与患者的耐药和癌症复发有关。这些发现揭示了细胞间力在化学敏感性中的调节作用,这可能被利用为癌症机械治疗的一个有希望的靶点。
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来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
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