KATP Channels Regulate Mitogenically Induced Proliferation in Primary Rat Hepatocytes and Human Liver Cell Lines

Abstract

To determine whether K ATP channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K ATP channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K ATP channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K ؉ channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K ؉ currents with K ATP channel properties. These K ؉ currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K ATP channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K ATP channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG2 cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K ATP channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K ATP channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis.

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach

“…In vivo production of PDX1 in liver also induces expression of the pancreas-type Gck [40]. The liver expresses the potassium inwardly rectifying channel, subfamily J, member 8 (Kcnj8; previously known as Kir6.1), a different subunit from the Kcnj11 found in pancreas [39]. In our hands, two forms of the potassium channel were expressed in transduced hepatocytes, while the control untransduced hepatocytes expressed only one (most probably Kcnj8).…”

“…1b), suggesting that PDX1-transduced hepatocytes could potentially produce mature insulin. Many constituents of the glucose-sensing beta cell cascade are identical or similar in both liver and beta cells, including Slc2a2, Gck [38], ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (Abcc8; previously known as sulfonylurea receptor 1 [Sur1]) and the potassium inwardly rectifying channel, subfamily J (Kcnj11; previously known as Kir6.2) [39]. Indeed, Slc2a2, the liver-type Gck, and Abcc8 were natively expressed in primary hepatocytes and were not affected by human PDX1 overexpression (Fig.…”

Liver-directed gene therapy of diabetic rats using an HVJ-E vector containing EBV plasmids expressing insulin and GLUT 2 transporter

“…27 Moreover, K ATP channels, which are the final effector molecules involved in insulin secretion in pancreatic beta cells, are normally expressed in liver cells. 28 However, K ATP channels in primary rat hepatocytes are not affected by voltage or Ca 2+ stimulation. 29 Thus, glucose-mediated ATP production and the subsequent reduced activity of functional K ATP channels are essential for the reconstruction of a glucose-responsive system.…”

Effects of Sulfonylureas on Tumor Growth: A Review of the Literature

“…2). Over the years, some evidence has shown the effects of glibenclamide on tumor growth arrest of different cancer types [12,22,23,30,31,33,34,38], even though the mechanisms of such antitumor activity were not completely clarified.…”