The Minerva Foundation Institute for Medical Research

Helsinki, Finland

The Minerva Foundation Institute for Medical Research

Helsinki, Finland
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Afrasiabi E.,Åbo Akademi University | Hietamaki M.,Åbo Akademi University | Viitanen T.,The Minerva Foundation Institute for Medical Research | Sukumaran P.,Åbo Akademi University | And 5 more authors.
Cellular Signalling | Year: 2010

The human ether-a-go-go related gene (HERG) potassium channel has elicited intense scientific interest due to its role in cardiac repolarization and its association with arrhythmia and sudden cardiac death. Increasing evidence indicates the involvement of HERG channels in the pathophysiology of cancer. In the present study we investigated the expression of HERG protein in MDA-MB-435S melanoma cells, and its importance in regulating cell proliferation and migration. Our results showed that HERG was expressed on protein and mRNA levels in MDA-MB-435S melanoma cells. In these cells blockade of HERG channels with the HERG blockers E 4301 or cisapride attenuated both proliferation and migration of the cells. Activation of HERG with PD118057 stimulated cell migration. Furthermore, HERG small interfering (si) RNA attenuated the proliferation and migration of the cells. Incubation of MDA-MB-435S cells with E 4301 decreased the phosphorylation of mitogen-activated protein (MAP) kinase and the expression of the c-fos transcription factor. In control experiments, overexpression of HERG channels in HEK-293 cells dramatically increased the proliferation and migration of the cells and blocking HERG in these cells attenuated both proliferation and migration. Our results indicate that MDA-MB-435S cells express HERG channels and blockade of HERG results in the attenuation of both proliferation and migration by a mechanism dependent, at least in part, on an inhibition of the MAP kinase/c-fos pathway. © 2009 Elsevier Inc. All rights reserved.

Ekokoski E.,University of Helsinki | Aitio O.,University of Helsinki | Tornquist K.,Åbo Akademi University | Tornquist K.,The Minerva Foundation Institute for Medical Research | And 2 more authors.
European Journal of Pharmaceutical Sciences | Year: 2010

HIV-1 Tat-peptide is widely used as a vector for cargo delivery into intact cells. As a cationic, arginine-rich peptide it can readily penetrate the plasma membrane and facilitate the penetration of impermeable bioactive molecules such as proteins, peptides, nucleic acids and drugs. Although at first considered as an inert vector, recent studies have however shown that it might have effects on its own on various cellular processes. In the present study we have investigated the effects of the Tat-peptide48-60 on two basic serine/threonine kinases, protein kinase C and A, since earlier studies have shown that certain arginine-rich peptides or proteins might have a modulatory effect on their activity. In in vitro studies, Tat-peptide inhibited PKC alpha in a concentration-dependent manner with an IC50-value of 22nM and PKA with an IC50-value of 1.2μM. The mode of inhibition was studied in the presence of increasing concentrations of a substrate peptide or ATP. Tat-peptide competed with the kinase substrates, however it did not compete with ATP. In a panel of 70 kinases Tat-peptide showed inhibitory activity at least towards other AGC-family kinases (PKB, SGK1, S6K1, MSK1), CAMK-family kinases (CAMK1 and MELK) and a STE family kinase (MKK1). In HeLa cells Tat-peptide inhibited the phorbol ester-evoked ERK1/2 phosphorylation suggesting that Tat inhibited PKC also in intact cells. In thyroid cells Tat-peptide attenuated sphingosylphosphorylcholine-evoked Ca2+-fluxes, which have earlier been shown to be dependent on PKC. Taken together, these results indicate that the Tat-peptide48-60 is a potent inhibitor which binds to the substrate binding site of the basophilic kinase domain. © 2010 Elsevier B.V.

Blom T.,Åbo Akademi University | Blom T.,University of Helsinki | Bergelin N.,Åbo Akademi University | Bergelin N.,The Minerva Foundation Institute for Medical Research | And 7 more authors.
BMC Cell Biology | Year: 2010

Background: Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates a multitude of cellular functions, including cell proliferation, survival, migration and angiogenesis. S1P mediates its effects either by signaling through G protein-coupled receptors (GPCRs) or through an intracellular mode of action. In this study, we have investigated the mechanism behind S1P-induced survival signalling.Results: We found that S1P protected cells from FasL-induced cell death in an NF-κB dependent manner. NF-κB was activated by extracellular S1P via S1P2receptors and Giprotein signaling. Our study also demonstrates that extracellular S1P stimulates cells to rapidly produce and secrete additional S1P, which can further amplify the NF-κB activation.Conclusions: We propose a self-amplifying loop of autocrine S1P with capacity to enhance cell survival. The mechanism provides increased understanding of the multifaceted roles of S1P in regulating cell fate during normal development and carcinogenesis. © 2010 Blom et al; licensee BioMed Central Ltd.

Tornquist K.,Åbo Akademi University | Tornquist K.,The Minerva Foundation Institute for Medical Research
Acta Physiologica | Year: 2012

In many cell types metabolites of sphingomyelin have a profound role in cellular signalling. One particular field where these derivatives have obtained a crucial role is calcium signalling. This is an interesting aspect on how lipids may wield their physiological role, as calcium is probably one of the most versatile signalling molecules in the cell, and modulation of calcium signalling may have profound effects on cellular physiology. In this review we discuss a novel aspect of sphingolipid signalling, i.e. the autocrine role of sphingosine 1-phosphate (S1P) in regulating calcium entry in thyroid cells. Although many investigations have highlighted the importance of S1P as a regulator of both calcium release from the endoplasmic reticulum and calcium entry through plasma membrane channels, the autocrine mechanism presented here introduces a new aspect of S1P signalling in thyroid cells. This mechanism may be physiologically relevant in many other cell types, including cancer cells. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society.

Kalhori V.,Åbo Akademi University | Kalhori V.,The Minerva Foundation Institute for Medical Research | Tornquist K.,Åbo Akademi University | Tornquist K.,The Minerva Foundation Institute for Medical Research
Molecular and Cellular Endocrinology | Year: 2015

The bioactive lipid sphingosine-1-phosphate (S1P) has emerged as a potent inducer of cancer cell migration and invasion. Previously, we have shown that S1P induces invasion of ML-1 follicular thyroid cancer cells via S1P receptors 1 and 3 (S1P1,3). Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes used by cells for degradation of the extracellular matrix during invasion and migration. In the present study, we examined the role of MMP2 and MMP9 for S1P-induced invasion of ML-1 cells, and found that S1P regulates the secretion and activity of MMP2 and MMP9 via S1P1,3. Both pharmacological inhibitors and siRNA knockdown of MMP2 and MMP9 could attenuate S1P-induced invasion. Additionally, we show that calpains and Rac1 mediate S1P-induced secretion of MMP2 and MMP9. In conclusion, MMP2 and MMP9 participate in S1P-evoked follicular ML-1 thyroid cancer cell invasion. © 2015 Elsevier Ireland Ltd.

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