Silencing of hSlo potassium channels in human osteosarcoma cells promotes tumorigenesis

Abstract

Potassium channels, the most diverse superfamily of ion channels, have recently emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large conductance Ca 21 -activated K 1 channels, often referred to as BK channels, are at the crossroads of several tumor-associated processes such as cell proliferation, survival, secretion and migration. Despite the high BK channel expression in osteosarcoma (OS), their function has not yet been investigated in this malignant bone pathology. Here, using stable RNA interference to reduce the expression of hSlo, the human pore-forming a-subunit of the BK channel, in human Cal72 OS cells, we show that BK channels play a functional role in carcinogenesis. Our results reveal for the first time that BK channels exhibit antitumoral properties in OS in vivo and affect the tumor microenvironment through the modulation of both chemokine expression and leukocyte infiltration. ' 2008 Wiley-Liss, Inc.Key words: osteosarcoma; ion channels; xenografts; chemokines; tumor microenvironmentThe development of cancer is a multistep process that usually occurs over many decades. This process encompasses the alteration of genes and/or proteins involved in fundamental cellular mechanisms like proliferation, apoptosis and differentiation. There is mounting evidence pointing to the involvement of ion channels in cancer progression. 1 The most compelling evidence regarding the involvement of ion channels in the transformation process relates to the over-expression of voltage-gated K channels in a variety of cancers. Among them are the large conductance Ca 21 -activated K 1 channels, often referred to as BK channels (for Big K). Indeed, we and others have shown that BK channels are a unique class of ion channels that are activated by a change in intracellular calcium, in voltage 2 and by a wide variety of molecules and molecular mechanisms including growth factors and hypoxia that, interestingly, are involved in carcinogenesis. [3][4][5][6] BK channels are expressed in a broad spectrum of cells in which they play a crucial role in neurotransmitter release, muscle relaxation 7,8 and diverse activities involved in tumor-associated processes such as cell proliferation, survival, secretion and migration. [9][10][11] Importantly, in human glioma, BK channels are significantly up-regulated, and their expression levels seem to correlate positively with tumor grade and poor patient prognosis. In vitro studies have suggested a role for BK channels in the control of glioma cell growth, survival and migration. 4,11 In addition glioma, we have shown a high level of BK expression in osteosarcoma (OS). 12 Altogether, these studies suggest an important role for BK in carcinogenesis and point to its potential value as a prognostic marker and/or a therapeutic target. To date, however, none of these aspects have been addressed in vivo.OS is the most common malignant bone tumor in children and adolescents. 13 OS is characterized by a hig...

Microarray gene expression profiling in meningiomas: Differential expression according to grade or histopathological subtype

“…Several other genes (SVEP1, COL8A1, LTBP2, SLO, SERPINF1, PDGFD, BMP4, LMO4, SFRP2 and SLC26A2), found to be downregulated in high-grade meningiomas in this study, have been previously reported with reduced expression in high-grade meningiomas (13). The inhibition of expression of some of these genes has been shown to be involved in tumorigenesis; this has been demonstrated for SLO in osteosarcoma (44), for SERPINF1 in breast cancer (45) and non-small cell lung cancer (46) and for LMO4 in several tumour types, including breast, prostate and pancreatic ductal adenocarcinomas (47). Furthermore, the frequent presence of ADAMTSL3 mutations has been reported in colorectal cancer (48) and decreased ADAMTSL3 mRNA expression, as observed in colorectal malignancy (48), may contribute to the progression of meningiomas.…”

Evidence for activation of BKCa channels by a known inhibitor of focal adhesion kinase, PF573228

“…Previous study showed that the knockdown with α-hSlo can induce a significant increase in tumor growth in vivo, suggesting a possible antitumoral effect of BK Ca channels in osteosarcoma (Cambien et al, 2008) and in tumor invasion Kraft et al, 2003;Kuhlmann et al, 2005;Ningaraj et al, 2009). Therefore, an effect of PF573228 on BK Ca channels functionally expressed in cells could likely have an impact on the functioning of the cells or tissues.…”

Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

“…BK channels assist breast, prostate and gliomas in tumor growth and spreading [101–108]. There are reports that BK channels don’t play a role in glioma cell division [109] and that genetic knock-down of BKα promotes osteosarcoma development [110]. So the role of BK channels in human cancer is a very complex one and may not be a universal one.…”