Lysophosphatidic acid receptors stimulate a Galpha(12/13)/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Galpha(12)Q231L, Galpha(13)Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (<1 mumol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Galpha(i)-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer.
"This is one of the major pathways activated within epithelial cells by the combination of TGFβ and matrix rigidity . In addition, small molecule inhibitors including CCG-1423 and its analogs block SRF/MRTFA signaling [191,192]. Namely, CCG-1423 blocks the interaction of MRTFA with importin alpha/beta 1 thus preventing the nuclear import of MRTFA . Furthermore, CCG-1423 has been shown to successfully inhibit TGFβ-induced expression of αSMA [102,104,194]. "
[Show abstract][Hide abstract] ABSTRACT: Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial-mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)-β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ-induced intracellular signaling cascades that are affected by cell- and tissue-level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.
Clinical and Translational Medicine 07/2014; 3(1):23. DOI:10.1186/2001-1326-3-23
"3). A drug inhibiting MKL1-dependent transcription, CCG-1423 (Evelyn et al., 2007), is already available, but more investigations should be performed to reveal a potential relevance to breast cancer treatment. "
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor alpha (ERα) is generally considered to be a good prognostic marker because almost 70% of ERα-positive tumors respond to anti-hormone therapies. Unfortunately, during cancer progression, mammary tumors can escape from estrogen control, resulting in resistance to treatment. In this study, we demonstrate that activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. The actin/MKL1 signaling pathway is silenced in differentiated ERα-positive breast cancer MCF-7 and T47D cell lines and active in ERα-negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells, which have undergone epithelial-mesenchymal transition. We showed that MKL1 activation in MCF-7 cells, either by modulating actin dynamics or using MKL1 mutants, down-regulates ERα expression and abolishes E2-dependent cell growth. Interestingly, the constitutively active form of MKL1 represses PR and HER2 expression in these cells and increases the expression of HB-EGF, TGFβ, and amphiregulin growth factors in an E2-independent manner. The resulting expression profile (ER-, PR-, HER2-) typically corresponds to the triple-negative breast cancer expression profile.
"We recently identified in high-throughput screens, a compound, CCG-1423, that blocks MRTF nuclear localization by interfering with the regulation of intranuclear actin polymerization mediated by microtubule-associated mono-oxygenase, calponin and LIM domain–containing 2 (MICAL-2) (Evelyn et al., 2007; Lundquist et al., 2014). CCG-1423 is more effective than ROCK inhibitors in reducing SRF-mediated transcription (Evelyn et al., 2007). Several groups have used this compound to interdict myofibroblast formation (Sandbo et al., 2009; Zhou et al., 2013), and it was recently shown to have in vivo activity in a chlorhexidine gluconate model of peritoneal fibrosis (Sakai et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc) or scleroderma, like many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF) and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explore the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF-SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in LPA- and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.
Journal of Pharmacology and Experimental Therapeutics 04/2014; 349(3). DOI:10.1124/jpet.114.213520 · 3.97 Impact Factor
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