The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells

Talman, Virpi; Amadio, Marialaura; Osera, Cecilia; Sorvari, Salla; Gennäs, Gustav Boije af; Yli‐Kauhaluoma, Jari; Rossi, Daniela; Govoni, Stefano; Collina, Simona; Ekokoski, Elina; Tuominen, Raimo K.; Pascale, Alessia

doi:10.1016/j.phrs.2013.04.008

Cited by 28 publications

(38 citation statements)

References 47 publications

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“…As shown previously Talman et al, 2013) and in this study, the cellular responses to isophthalates correlate closely with the binding affinity of the isophthalate to the C1 domain. However, since the antiproliferative and morphological responses in HeLa cells seem to be independent of PKC, it is probable that they are mediated by some other DAG/phorbol ester-responsive protein(s).…”

Section: Discussionsupporting

confidence: 89%

“…Both PKC activators and inhibitors bear the potential of becoming cancer therapeutics, since the role of PKC isoforms in cancer depends on the original tissue and on the cell type (Griner and Kazanietz, 2007;Hofmann, 2004). In our previous studies in HeLa and SH-SY5Y cells the isophthalate HMI-1a3 induced phosphorylation of ERK1/2, and the effect was inhibited by the pan-PKC inhibitor Gö6983, showing that HMI-1a3 functions as a PKC-activator Talman et al, 2013). HMI-1a3 was able to inhibit HeLa cell proliferation and to induce a distinct morphological change, cell elongation, in HeLa cells .…”

Section: Discussionmentioning

confidence: 97%

“…Since our previous data suggested that HMI-1a3 induces PKC-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa and SH-SY5Y cells (Gonelli et al, 2009;Talman et al, 2013), we investigated the roles of PKC and ERK1/2 pathways in HMI-1a3-induced cytotoxicity, cell elongation and antiproliferative effects by using pharmacological tools. Inhibition of PKC by the pan-PKC inhibitor Gö6983, activation of PKC by PMA, or MEK inhibition by U0126 were unable to protect HeLa cells from HMI-1a3-induced toxicity (Fig.…”

Section: Effects Of Pharmacological Modulation Of Pkc or The Erk1/2 Pmentioning

confidence: 99%

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

Talman

Gateva

Ahti

et al. 2014

European Journal of Pharmaceutical Sciences

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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 coexposure to 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 GTPasemediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of β2-chimaerin, protein kinase D (PKD) and MRCK, which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI1a3-induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 97%

Section: Effects Of Pharmacological Modulation Of Pkc or The Erk1/2 Pmentioning

confidence: 99%

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

Talman

Gateva

Ahti

et al. 2014

European Journal of Pharmaceutical Sciences

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“…Cells were processed according to Talman et al [36] with minor modifications. Briefly, cells plated (300,000/well) on glass coverslips, previously coated with 0.01% poly-L-lysine, were treated for 48 h with 10-50 μg/mL of GNS/PEG5000 and of PAH@GNS/PEGCOOH.…”

Section: Two-photon Luminescence Microscopy and Cellular Uptakementioning

confidence: 99%

Gold nanostars coated with neutral and charged polyethylene glycols: A comparative study of in-vitro biocompatibility and of their interaction with SH-SY5Y neuroblastoma cells

Pallavicini

Cabrini

Cavallaro

et al. 2015

Journal of Inorganic Biochemistry

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“…To confirm whether the sPIF-induced reduction of apoptosis was dependent on PKA/PKC signaling, pharmacological inhibitors specific against PKA (H89) and PKC (Gö6983) 53,54 were used. As shown in Figure 3c, sPIF-induced neuronal survival was abolished in the presence of H89 and Gö6983, consistent with a PKA/PKC-mediated mechanism.…”

mentioning

confidence: 99%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

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The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells

Cited by 28 publications

References 47 publications

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

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

Gold nanostars coated with neutral and charged polyethylene glycols: A comparative study of in-vitro biocompatibility and of their interaction with SH-SY5Y neuroblastoma cells

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

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