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Rosiglitazone selectively inhibits K(ATP) channels by acting on the K(IR) 6 subunit.

ABSTRACT: Rosiglitazone is an anti-diabetic drug acting as an insulin sensitizer. We recently found that rosiglitazone also inhibits the vascular isoform of ATP-sensitive K(+) channels and compromises vasodilatory effects of ?-adrenoceptor activation and pinacidil. As its potency for the channel inhibition is in the micromolar range, rosiglitazone may be used as an effective K(ATP) channel inhibitor for research and therapeutic purposes. Therefore, we performed experiments to determine whether other isoforms of K(ATP) channels are also sensitive to rosiglitazone and what their sensitivities are.K(IR) 6.1/SUR2B, K(IR) 6.2/SUR1, K(IR) 6.2/SUR2A, K(IR) 6.2/SUR2B and K(IR) 6.2?C36 channels were expressed in HEK293 cells and were studied using patch-clamp techniques.Rosiglitazone inhibited all isoforms of K(ATP) channels in excised patches and in the whole-cell configuration. Its IC(50) was 10?µmol·L(-1) for the K(IR) 6.1/SUR2B channel and ?45?µmol·L(-1) for K(IR) 6.2/SURx channels. Rosiglitazone also inhibited K(IR) 6.2?C36 channels in the absence of the sulphonylurea receptor (SUR) subunit, with potency (IC(50) = 45?µmol·L(-1) ) almost identical to that for K(IR) 6.2/SURx channels. Single-channel kinetic analysis showed that the channel inhibition was mediated by augmentation of the long-lasting closures without affecting the channel open state and unitary conductance. In contrast, rosiglitazone had no effect on K(IR) 1.1, K(IR) 2.1 and K(IR) 4.1 channels, suggesting that the channel inhibitory effect is selective for K(IR) 6.x channels.These results suggest a novel K(ATP) channel inhibitor that acts on the pore-forming K(IR) 6.x subunit, affecting the channel gating.

SUBMITTER: Yu L

PROVIDER: S-EPMC3448911 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Rosiglitazone selectively inhibits K(ATP) channels by acting on the K(IR) 6 subunit.

Yu Lei L Jin Xin X Cui Ningren N Wu Yang Y Shi Zhenda Z Zhu Daling D Jiang Chun C

British journal of pharmacology 20120901 1

<h4>Background and purpose</h4>Rosiglitazone is an anti-diabetic drug acting as an insulin sensitizer. We recently found that rosiglitazone also inhibits the vascular isoform of ATP-sensitive K(+) channels and compromises vasodilatory effects of β-adrenoceptor activation and pinacidil. As its potency for the channel inhibition is in the micromolar range, rosiglitazone may be used as an effective K(ATP) channel inhibitor for research and therapeutic purposes. Therefore, we performed experiments t ...[more]

PMID: 22394376

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Project description:Here, we provide evidence that high ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anticancer therapy, especially for preventing tumor progression. More specifically, we isolated a subpopulation of ATP-high cancer cells which are phenotypically aggressive and demonstrate increases in proliferation, stemness, anchorage-independence, cell migration, invasion and multi-drug resistance, as well as high antioxidant capacity. Clinically, these findings have important implications for understanding treatment failure and cancer cell dormancy. Using bioinformatic analysis of patient samples, we defined a mitochondrial-related gene signature for metastasis, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). The relationship between ATP5F1C protein expression and metastasis was indeed confirmed by immunohistochemistry. Next, we used MDA-MB-231 cells as a model system to functionally validate these findings. Importantly, ATP-high MDA-MB-231 cells showed a nearly fivefold increase in metastatic capacity in vivo. Consistent with these observations, ATP-high cells overexpressed (i) components of mitochondrial complexes I-V, including ATP5F1C, and (ii) markers associated with circulating tumor cells (CTCs) and metastasis, such as EpCAM and VCAM1. Knockdown of ATP5F1C expression significantly reduced ATP-production, anchorage-independent growth, and cell migration, as predicted. Similarly, therapeutic administration of the FDA-approved drug, Bedaquiline, downregulated ATP5F1C expression in vitro and prevented spontaneous metastasis in vivo. In contrast, Bedaquiline had no effect on the growth of non-tumorigenic mammary epithelial cells (MCF10A) or primary tumors in vivo. Taken together, our results suggest that mitochondrial ATP depletion is a new therapeutic strategy for metastasis prophylaxis, to avoid treatment failure. In summary, we conclude that mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

Project description:The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as "mitocans" to induce cancer-specific mitophagy.Abbreviations: ATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type.

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Rosiglitazone selectively inhibits K(ATP) channels by acting on the K(IR) 6 subunit.

Publications

Rosiglitazone selectively inhibits K(ATP) channels by acting on the K(IR) 6 subunit.

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