Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

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• 作者：Virpi Talman^a ; ^{virpi.talman@helsinki.fi" class="auth_mail} ; Gergana Gateva^b ; Marja Ahti^a ; Elina Ekokoski^a ; ¹ ; Pekka Lappalainen^b ; Raimo K. Tuominen^a
• 关键词：Chelerythrine (PubChem CID ; 72311) ; CID755673 (PubChem CID ; 755673) ; Gö ; 6983 (PubChem CID ; 3499) ; Phorbol 12 ; 13-dibutyrate (PubChem CID ; 37783) ; Phorbol 12-myristate 13-acetate (PubChem CID ; CID 27924) ; U0126 (PubChem CID ; 3006531)
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：13 May, 2014
• 年：2014
• 卷：55
• 期：Complete
• 页码：46-57
• 全文大小：2871 K

文摘

Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) and other DAG effector proteins, is considered a potential cancer drug target. Derivatives of 5-(hydroxymethyl)isophthalic acid are a novel group of C1 domain ligands with antiproliferative and differentiation-inducing effects. Our previous work showed that these isophthalate derivatives exhibit antiproliferative and elongation-inducing effects in HeLa human cervical cancer cells. In this study we further characterized the effects of bis(3-trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on HeLa cell proliferation and morphology. HMI-1a3-induced cell elongation was accompanied with loss of focal adhesions and actin stress fibers, and exposure to HMI-1a3 induced a prominent relocation of cofilin-1 into the nucleus regardless of cell phenotype. The antiproliferative and morphological responses to HMI-1a3 were not modified by pharmacological inhibition or activation of PKC, or by RNAi knock-down of specific PKC isoforms, suggesting that the effects of HMI-1a3 were not mediated by PKC. Genome-wide gene expression microarray and gene set enrichment analysis suggested that, among others, HMI-1a3 induces changes in small GTPase-mediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of 尾2-chimaerin, protein kinase D (PKD) and myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI-1a3-induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology.