Vázquez-Prado José, Bracho-Valdés Ismael, Cervantes-Villagrana Rodolfo Daniel, Reyes-Cruz Guadalupe
Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico
Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico.
Mol Pharmacol. 2016 Nov;90(5):573-586. doi: 10.1124/mol.116.105338. Epub 2016 Sep 16.
Cancer cells and stroma cells in tumors secrete chemotactic agonists that exacerbate invasive behavior, promote tumor-induced angiogenesis, and recruit protumoral bone marrow-derived cells. In response to shallow gradients of chemotactic stimuli recognized by G protein-coupled receptors (GPCRs), Gβγ-dependent signaling cascades contribute to specifying the spatiotemporal assembly of cytoskeletal structures that can dynamically alter cell morphology. This sophisticated process is intrinsically linked to the activation of Rho GTPases and their cytoskeletal-remodeling effectors. Thus, Rho guanine nucleotide exchange factors, the activators of these molecular switches, and their upstream signaling partners are considered participants of tumor progression. Specifically, phosphoinositide-3 kinases (class I PI3Ks, β and γ) and P-Rex1, a Rac-specific guanine nucleotide exchange factor, are fundamental Gβγ effectors in the pathways controlling directionally persistent motility. In addition, GPCR-dependent chemotactic responses often involve endosomal trafficking of signaling proteins; coincidently, endosomes serve as signaling platforms for Gβγ In preclinical murine models of cancer, inhibition of Gβγ attenuates tumor growth, whereas in cancer patients, aberrant overexpression of chemotactic Gβγ effectors and recently identified mutations in Gβ correlate with poor clinical outcome. Here we discuss emerging paradigms of Gβγ signaling in cancer, which are essential for chemotactic cell migration and represent novel opportunities to develop pathway-specific pharmacologic treatments.
肿瘤中的癌细胞和基质细胞会分泌趋化激动剂，这些激动剂会加剧侵袭行为、促进肿瘤诱导的血管生成，并募集源自骨髓的促肿瘤细胞。响应由G蛋白偶联受体（GPCRs）识别的趋化刺激浅梯度，Gβγ依赖性信号级联有助于确定细胞骨架结构的时空组装，这种组装可动态改变细胞形态。这一复杂过程与Rho GTP酶及其细胞骨架重塑效应器的激活内在相关。因此，Rho鸟嘌呤核苷酸交换因子，这些分子开关的激活剂及其上游信号伙伴被认为是肿瘤进展的参与者。具体而言，磷酸肌醇-3激酶（I类PI3K，β和γ）和P-Rex1，一种Rac特异性鸟嘌呤核苷酸交换因子，是控制定向持续运动的信号通路中的基本Gβγ效应器。此外，GPCR依赖性趋化反应通常涉及信号蛋白的内体运输；巧合的是，内体充当Gβγ的信号平台。在临床前小鼠癌症模型中，抑制Gβγ可减弱肿瘤生长，而在癌症患者中，趋化性Gβγ效应器的异常过表达以及最近发现的Gβ突变与不良临床结果相关。在这里，我们讨论癌症中Gβγ信号传导的新兴模式，这些模式对于趋化性细胞迁移至关重要，并代表了开发通路特异性药物治疗的新机会。
