Inhibition du canal SK3 et du développement de métastases par un ether-lipide synthétique

Il a été mis en évidence que le canal SK3 est un médiateur de la migration de cellules cancéreuses mammaires, une propriété essentielle à la formation de métastases. Par ailleurs, ce canal est inhibé par l édelfosine, un éther-lipide ayant des propriétés anti-tumorales in vitro mais son usage en clinique a été abandonné en raison d effets secondaires. Une première partie de ce travail a permis de déterminer les parties de l édelfosine nécessaires à l inhibition du canal SK3 et de la migration cellulaire. Ceci nous a permis de sélectionner l Ohmline (1-O-Hexadécyl-2-O-Méthyl-sn-glycéro-lactose), un analogue non toxique de l édelfosine qui conserve son activité inhibitrice de SK3 et de la migration. Dans un deuxième temps, nous avons testé ce lipide dans un modèle murin de développement tumoral et nous avons montré qu il réduisait le développement des métastases sans modifier la tumeur primaire. En conclusion, nous avons décrit l Ohmline qui est le premier inhibiteur lipidique de SK3 et qui pourrait devenir le premier membre d une famille de composés lipidiques inhibiteurs de la formation de métastases.It has been shown that SK3 channel was a mediator of breast cancer cells migration, a fundamental property for metastasis formation. In addition, edelfosine inhibits SK3 channel. This ether-lipid owns a high anti cancerous potential in vitro but its clinical use was hampered by some side effects, Firstly, we showed the structural parts of edelfosine required for SK3 channel inhibition and cell motility inhibition. Moreover, we selected Ohmline (1-O-Hexadécyl-2-O-Méthyl-sn-glycéro-lactose), an edlefosine s analogue that preserves SK3 channel and motility inhibitory properties. Secondly, we evaluated this lipid on tumor development in nude mice model. We showed that this lipid reduces metastasis formation without effect on primary tumor. To conclude, we described Ohmline, the first lipid inhibitor of SK3. This compound should become the first member of a new family of metastasis lipid inhibitors.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF

Voltage-gated sodium channels: new targets in cancer therapy?

Early detection and treatment of cancers have increased survival and improved clinical outcome. The development of metastases is often associated with a poor prognostic of survival. Finding early markers of metastasis and developing new therapies against their development is a great challenge. Since a few years, there is more evidence that ionic channels are involved in the oncogenic process. Among these, voltage-gated sodium channels expressed in non-nervous or non-muscular organs are often associated with the metastatic behaviour of different cancers. The aim of this review is to describe the current knowledge on the functional expression of voltage-gated sodium channels and their biological roles in different cancers such as prostate, breast, lung (small cells and non-small cells) and leukaemia. In the conclusion, we develop conceptual approaches to understand how such channels can be involved in the metastatic process and conclude that blockers targeted toward these channels are promising new therapeutic solutions against metastatic cancers

KCa and Ca2+ channels: The complex thought

AbstractPotassium channels belong to the largest and the most diverse super-families of ion channels. Among them, Ca2+-activated K+ channels (KCa) comprise many members. Based on their single channel conductance they are divided into three subfamilies: big conductance (BKCa), intermediate conductance (IKCa) and small conductance (SKCa; SK1, SK2 and SK3). Ca2+ channels are divided into two main families, voltage gated/voltage dependent Ca2+ channels and non-voltage gated/voltage independent Ca2+ channels. Based on their electrophysiological and pharmacological properties and on the tissue where there are expressed, voltage gated Ca2+ channels (Cav) are divided into 5 families: T-type, L-type, N-type, P/Q-type and R-type Ca2+. Non-voltage gated Ca2+ channels comprise the TRP (TRPC, TRPV, TRPM, TRPA, TRPP, TRPML and TRPN) and Orai (Orai1 to Orai3) families and their partners STIM (STIM1 to STIM2). A depolarization is needed to activate voltage-gated Ca2+ channels while non-voltage gated Ca2+ channels are activated by Ca2+ depletion of the endoplasmic reticulum stores (SOCs) or by receptors (ROCs). These two Ca2+ channel families also control constitutive Ca2+ entries. For reducing the energy consumption and for the fine regulation of Ca2+, KCa and Ca2+ channels appear associated as complexes in excitable and non-excitable cells. Interestingly, there is now evidence that KCa–Ca2+ channel complexes are also found in cancer cells and contribute to cancer-associated functions such as cell proliferation, cell migration and the capacity to develop metastases. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau

Data pertaining to aberrant intracellular calcium handling during androgen deprivation therapy in prostate cancer

The data generated here in relates to the research article “CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer”. A model of prostate cancer (PCa) progression to castration resistance was employed, with untreated androgen sensitive LNCaP cell line alongside two androgen deprived (bicalutamide) sublines, either 10 days (LNCaP-ADT) or 2 years (LNCaP-ABL) treatment, in addition to androgen insensitive PC3. With this PCa model, qPCR was used to examined fold change in markers linked to androgen resistance, androgen receptor (AR) and neuron specific enolase (NSE), observing an increase under androgen deprivation. In addition, the gene expression of a range of calcium channels was measured, with only the L-type Voltage gated calcium channel, CACNA1D, demonstrating an increase during androgen deprivation. With CACNA1D knockdown the channel was found not to influence the gene expression of calcium channels, ORAI1 and STIM1. The calcium channel blocker (CCB), nifedipine, was employed to determine the impact of CaV1.3 on the observed store release and calcium entry measured via Fura-2AM ratiometric dye in our outlined PCa model. In both the presence and absence of androgen deprivation, nifedipine was found to have no impact on store release induced by thapsigargin (Tg) in 0mM Ca(2+) nor store operated calcium entry (SOCE) following the addition of 2mM Ca(2+). However, CACNA1D siRNA knockdown was able to reduce SOCE in PC3 cells. The effect of nifedipine on CaV1.3 in PCa biology was measured through cell proliferation assay, with no observed change in the presence of CCB. While siCACNA1D reduced PC3 cell proliferation. This data can be reused to inform new studies investigating altered calcium handling in androgen resistant prostate cancer. It provides insight into the mechanism of CaV1.3 and its functional properties in altered calcium in cancer, which can be of use to researchers investigating this channel in disease. Furthermore, it could be helpful in interpreting studies investigating CCB's as a therapeutic and in the development of future drugs targeting CaV1.3

Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells.

International audienceExpression of the antimicrobial peptide hCAP18/LL-37 is associated to malignancy in various cancer forms, stimulating cell migration and metastasis. We report that LL-37 induces migration of three cancer cell lines by activating the TRPV2 calcium-permeable channel and recruiting it to pseudopodia through activation of the PI3K/AKT pathway. Ca2+ entry through TRPV2 cooperated with a K+ efflux through the BKCa channel. In a panel of human breast tumors, the expression of TRPV2 and LL-37 was found to be positively correlated. The D-enantiomer of LL-37 showed identical effects as the L-peptide, suggesting that no binding to a specific receptor was involved. LL-37 attached to caveolae and pseudopodia membranes and decreased membrane fluidity, suggesting that a modification of the physical properties of the lipid membrane bilayer was the underlying mechanism of its effects

Insights into the mechanisms governing P01 scorpion toxin effect against U87 glioblastoma cells oncogenesis

The emerging concept of small conductance Ca2+-activated potassium channels (SKCa) as pharmacological target for cancer treatment has significantly increased in recent years. In this study, we isolated the P01 toxin from Androctonus australis (Aa) scorpion venom and investigated its effect on biological properties of glioblastoma U87, breast MDA-MB231 and colon adenocarcinoma LS174 cancer cell lines. Our results showed that P01 was active only on U87 glioblastoma cells. It inhibited their proliferation, adhesion and migration with IC50 values in the micromolar range. We have also shown that P01 reduced the amplitude of the currents recorded in HEK293 cells expressing SK2 channels with an IC50 value of 3 pM, while it had no effect on those expressing SK3 channels. The investigation of the SKCa channels expression pattern showed that SK2 transcripts were expressed differently in the three cancer cell lines. Particularly, we highlighted the presence of SK2 isoforms in U87 cells, which could explain and rely on the specific activity of P01 on this cell line. These experimental data highlighted the usefulness of scorpion peptides to decipher the role of SKCa channels in the tumorigenesis process, and develop potential therapeutic molecules targeting glioblastoma with high selectivity

Orai1/KCa/SigmaR1 complex, the cancer cell suicide squad

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Regulation of human dendritic cell immune functions by ion channels

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