Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids?

Guéguinou, Maxime; Gambade, Audrey; Félix, Romain; Chantôme, Aurélie; Fourbon, Yann; Bougnoux, Philippe; Weber, Günther; Potier-Cartereau, Marie; Vandier, Christophe

doi:10.1016/j.bbamem.2014.10.036

Cited by 59 publications

(60 citation statements)

References 274 publications

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“…This channel is expressed as a complex with the Orai1 calcium channel in caveolae lipid rafts . This complex was not observed in several non-tumor cells and seems specific to cancer cells (Gueguinou, et al, 2014). Because of this novel and non-physiological function of SK3 channel, a role of SK3 channel was hypothesized in the formation of metastases.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

“…Membrane nanodomains named lipid rafts, enriched in sterols and sphingolipids have been found to play a major role for the correct functioning of several cell survival signaling pathways Simons & Toomre, 2000) as well as of transporters and ion channels (Best & Kamp, 2012;Gueguinou, et al, 2014;Mollinedo, 2012;Pani & Singh, 2009;Rosenhouse-Dantsker, et al, 2012), including SK3 channel . In addition, lipid rafts have also been found to mediate death receptor signaling favoring the triggering of apoptosis (Gajate, et al, 2004;Gajate & Mollinedo, 2015b;.…”

Section: Importance Of Lipid Rafts For Edelfosine and Ohmline's Antitmentioning

confidence: 99%

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Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Jaffrès

Gajate

Bouchet

et al. 2016

Pharmacology & Therapeutics

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Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed.

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Section: Accepted Manuscriptmentioning

confidence: 98%

Section: Importance Of Lipid Rafts For Edelfosine and Ohmline's Antitmentioning

confidence: 99%

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Jaffrès

Gajate

Bouchet

et al. 2016

Pharmacology & Therapeutics

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“…In tumor cells these complexes contribute to several cancer associated functions such as cell proliferation, cell migration and the capacity to develop metastases [11, 12]. We have proposed that theses complexes are spatially segregated in nanodomains such as lipid-rafts [13]. This particular subcellular localization has been observed in the case of the TRPC1 channelosome [14], and many ion channels have been found to be associated with in lipid-rafts [15].…”

Section: Introductionmentioning

confidence: 99%

SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline

et al. 2016

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BackgroundBarely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells.ResultsIn the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action.ConclusionsThis study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.

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“…In cancer cells, the dysregulation of K Ca channels is associated with key aspects of proliferation, migration, and invasion during metastasis [19,20,21]. Based on single-channel conductance, K Ca channels have been classified into large-conductance K Ca 1.1, small-conductance K Ca 2.x (2.1–2.3), and intermediate-conductance K Ca 3.1 channels.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

Khatun

Fujimoto

Kurihara

et al. 2016

IJMS

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Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.

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Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids?

Cited by 59 publications

References 274 publications

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

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