Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells

Sørensen, Belinda Halling; Dam, Celina Støving; Stürup, Stefan; Lambert, Ian Henry

doi:10.1016/j.jinorgbio.2016.04.004

Cited by 54 publications

(65 citation statements)

References 64 publications

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“…Triggered by the findings that LRRC8 protein downregulation increases cisplatin resistance [10][11][12][13] and that LRRC8D is essential for blasticidin uptake 14 we tested cisplatin and blasticidin effects on oocytes expressing fluorescently tagged constitutively active 8A-VFP/8E-mCh and 8A-VFP/8D-mCh channels.…”

Section: Resultsmentioning

confidence: 99%

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Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

et al. 2017

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LRRC8 proteins have been shown to underlie the ubiquitous volume regulated anion channel (VRAC). VRAC channels are composed of the LRRC8A subunit and at least one among the LRRC8B-E subunits. In addition to their role in volume regulation, LRRC8 proteins have been implicated in the uptake of chemotherapeutic agents. We had found that LRRC8 channels can be conveniently expressed in Xenopus oocytes, a system without endogenous VRAC activity. The fusion with fluorescent proteins yielded constitutive activity for A/C, A/D and A/E heteromers. Here we tested the effect of the anticancer drug cisplatin on LRRC8A-VFP/8E-mCherry and LRRC8A-VFP/8D-mCherry co-expressing oocytes. Incubation with cisplatin dramatically activated currents for both subunit combinations, confirming that VRAC channels provide an uptake pathway for cisplatin and that intracellular cisplatin accumulation strongly activates the channels. Thus, specific activators of LRRC8 proteins might be useful tools to counteract chemotherapeutic drug resistance.

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Section: Resultsmentioning

confidence: 99%

“…cisplatin). [9][10][11][12][13] Additionally, patients with a low LRRC8D gene expression in their ovarian cancers displayed reduced survival. 10 Similarly, LRRC8D expression was shown to be essential for the cytotoxic effect of the antibiotic blasticidin S.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

et al. 2017

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“…26,27 Recently, cisplatin resistance in other cell lines has been shown to be associated with loss of LRRC8D 16 and with reduced expression of LRRC8A. 28,29 Here, we examined whether deficiency of VSOR current generation in KCP-4 cells is related to a lack of or insufficient expression of LRRC8A or LRRC8D. When expression of human LRRC8A mRNA (LRRC8A) was compared between KCP-4 and KB cells by RT-PCR, it was nearly equal (KCP-4/KB D 94.2 §0 .9%: Fig.…”

Section: Lrrc8a/d/e Is Abundantly Expressed In a Vsor-deficient Cell mentioning

confidence: 99%

Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)

et al. 2016

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The broadly expressed volume-sensitive outwardly rectifying anion channel (VSOR, also called VRAC) plays essential roles in cell survival and death. Recent findings have suggested that LRRC8A is a core component of VSOR in human cells. In the present study, VSOR currents were found to be largely reduced by siRNA against LRRC8A in mouse C127 cells as well. In contrast, LRRC8A knockdown never affected activities of 4 other types of anion channel activated by acid, Ca 2C , patch excision or cAMP. While cisplatin-resistant KCP-4 cells poorly expressed endogenous VSOR activity, molecular expression levels of LRRC8A, LRRC8D and LRRC8E were indistinguishable between VSOR-deficient KCP-4 cells and the parental VSOR-rich KB cells. Furthermore, overexpression of LRRC8A alone or together with LRRC8D or LRRC8E in KCP-4 cells failed to restore VSOR activity. These results show that deficiency of VSOR currents in KCP-4 cells is not due to insufficient expression of the LRRC8A/D/ E gene, suggesting an essential involvement of some other factor(s), and indicate that further study is required to better understand the complexities of the molecular determinants of VSOR, including the precise role of LRRC8 proteins.

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“…The Organic Cation Transporter 1 and 2 (OCT1/2), multidrug and toxin extrusion protein 1-3 (MATE1-3), and multidrug resistance-associated protein 1/2 (MRP1/2) have also been assigned a role in the accumulation and release of cisplatin, but their influence on resistance is not fully understood [27]. However, with respect to MRP1 and MRP4 it has been demonstrated that increased expression and altered N-linked glycosylation in the oxaliplatin-resistant human ovarian carcinoma IGROV-1 cell line are associated with reduced accumulation of the platinum drugs and resistance to oxaliplatin and cisplatin [28].…”

Section: Cellular Cisplatin Accumulationmentioning

confidence: 99%

“…However, it was only in 2014 that members of the leucine-rich repeat-containing 8 (LRRC8) protein family were first identified as being responsible for VRAC activity, i.e., for the volume-sensitive chloride current (I Cl,swell ) and swelling-induced loss of neurotransmitters and organic osmolytes [33,34,35,36,37,38,39]. Interestingly, it has now been demonstrated that VRACs also facilitate the accumulation of cisplatin and carboplatin, but not oxaliplatin [27,40]. …”

Section: Cellular Cisplatin Accumulationmentioning

confidence: 99%

Facilitating the Cellular Accumulation of Pt-Based Chemotherapeutic Drugs

Lambert

Sørensen

2018

IJMS

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Cisplatin, carboplatin, and oxaliplatin are Pt-based drugs used in the chemotherapeutic eradication of cancer cells. Although most cancer patient cells initially respond well to the treatment, the clinical effectiveness declines over time as the cancer cells develop resistance to the drugs. The Pt-based drugs are accumulated via membrane-bound transporters, translocated to the nucleus, where they trigger various intracellular cell death programs through DNA interaction. Here we illustrate how resistance to Pt-based drugs, acquired through limitation in the activity/subcellular localization of canonical drug transporters, might be circumvented by the facilitated uptake of Pt-based drug complexes via nanocarriers/endocytosis or lipophilic drugs by diffusion.

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Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells

Cited by 54 publications

References 64 publications

Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)

Facilitating the Cellular Accumulation of Pt-Based Chemotherapeutic Drugs

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