Solyakov L, Sayan E, Riley J, Pointon A, Tobin A B
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.
Oncogene. 2009 Oct 15;28(41):3619-30. doi: 10.1038/onc.2009.225. Epub 2009 Aug 3.
G-protein-coupled receptors (GPCRs) have been extremely successful drug targets for a multitude of diseases from heart failure to depression. This superfamily of cell surface receptors have not, however, been widely considered as a viable target in cancer treatment. In this study we show that a classical G(q/11)-coupled GPCR, the M(3)-muscarinic receptor, was able to regulate apoptosis through receptors that are endogenously expressed in the human neuroblastoma cell line, SH-SY5Y, and when ectopically expressed in Chinese hamster ovary (CHO) cells. Stimulation of the M(3)-muscarinic receptor was shown to inhibit the ability of the DNA-damaging chemotherapeutic agent, etoposide, from mediating apoptosis. This protective response in CHO cells correlated with the ability of the receptor to regulate the expression levels of p53. In contrast, stimulation of endogenous muscarinic receptors in SH-SY5Y cells did not regulate p53 expression but rather was able to inhibit p53 translocation to the mitochondria and p53 phosphorylation at serine 15 and 37. This study suggests the possibility that a GPCR can regulate the apoptotic properties of a chemotherapeutic DNA-damaging agent by regulating the expression, subcellular trafficking and modification of p53 in a manner that is, in part, dependent on the cell type.
G蛋白偶联受体（GPCRs）已成为从心力衰竭到抑郁症等多种疾病极为成功的药物靶点。然而，这类细胞表面受体超家族在癌症治疗中尚未被广泛视为可行的靶点。在本研究中，我们发现一种经典的G（q/11）偶联GPCR，即M（3）-毒蕈碱受体，能够通过在人神经母细胞瘤细胞系SH-SY5Y中内源性表达的受体来调节细胞凋亡，并且当在中国仓鼠卵巢（CHO）细胞中异位表达时也具有这种能力。研究表明，刺激M（3）-毒蕈碱受体可抑制DNA损伤化疗药物依托泊苷介导细胞凋亡的能力。CHO细胞中的这种保护反应与该受体调节p53表达水平的能力相关。相比之下，刺激SH-SY5Y细胞中的内源性毒蕈碱受体并不会调节p53的表达，而是能够抑制p53向线粒体的转位以及p53在丝氨酸15和37位点的磷酸化。本研究表明，GPCR有可能通过部分依赖于细胞类型的方式调节p53的表达、亚细胞定位和修饰，从而调控化疗DNA损伤药物的凋亡特性。
