Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Int J Cancer. 2012 Jun 1;130(11):2539-48. doi: 10.1002/ijc.26257. Epub 2011 Aug 12.
In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ-collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer.
在结直肠癌中，抗肿瘤的鸟苷酸环化酶 C（GCC）信号通路存在缺陷，反映了内源性激素表达下调导致配体缺失。尽管该信号转导系统的近端细胞内介质，包括环鸟苷酸（cGMP）和 cGMP 依赖性蛋白激酶（PKG），已经得到很好的描述，但其远端效应器的功能意义仍然模糊不清。通过血管扩张刺激磷蛋白（VASP）调节配体依赖性 GCC 信号，VASP 是一种参与膜突起动力学的肌动蛋白结合蛋白，其在结直肠肿瘤中的表达下调，从而严重降低了 cGMP 依赖性 VASP 磷酸化水平。GCC 激动剂恢复 cGMP 依赖性 VASP 磷酸化可抑制人结肠癌细胞中运动（丝状伪足）和侵袭（侵袭伪足）肌动蛋白基细胞器的数量和长度。膜细胞器的解体反映了 VASP Ser239 的特异性磷酸化，这是 cGMP/PKG 的首选位点，以及 VASP 从肿瘤细胞突起中的快速去除。重要的是，VASP Ser239 磷酸化抑制了侵袭伪足的蛋白水解功能，反映为抑制了癌细胞消化嵌入 Matrigel 的 DQ-胶原 IV 的能力。这些结果表明，VASP Ser239 磷酸化作为一种有效的机制，可对抗促进结肠癌侵袭和转移的肿瘤细胞形状，这是一种以前未被认识的作用。通过 VASP 重建生理 cGMP 电路，反过来又代表了一种有吸引力的靶向治疗方法，适用于结直肠癌患者。
