Activation of the Na+/H+-exchanger is NIH 3T3 fibroblasts expressing the Ha-ras oncogene requires stimulated calcium influx and is associated with rearrangement of the actin cytoskeleton

Ritter, Matthew R.; Wöll, Ewald; Dartsch, Peter C.; Gschwentner, Martin; Haller, Thomas; Zwierzina, Heinz; Lang, Frederick

doi:10.1016/0959-8049(95)99873-x

Cited by 10 publications

(12 citation statements)

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“…The oscillations of Cai are crucial to the regulation of cell proliferation, since their inhibition abrogates mitotic activity of these cells in growth factor depleted media and annihilates events tightly engaged with the transformation of the cells like activation of the Na As shown in this study, simvastatin indeed inhibits ras induced cytoskeletal remodeling (figure 4) and intracellular alkalinization, events depending on the occurrence of Cai oscillations [16]. The cytosolic alkalinization has been shown to be due to activation of the Na + / H + exchanger (NHE).…”

Section: Discussionmentioning

confidence: 85%

“…The pulsatile release of calcium is triggerd by calcium entry from the extracellular space (calcium induced calcium release) and can be abrogated by inhibition of calcium uptake/release from internal stores and/or by inhibition of cellular calcium influx. As a matter of fact one of the immediate responses of the cells to Ha-ras oncogene expression is the stimulation of a calcium conductive pathway [16,21]. It has been shown that the rate of calcium entry is a main determinant for the frequency of the oscillations and that the expression of nuclear transcription factors is regu- Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Data acquisition was performed using Pulse (HEKA, Germany), data analysis using Datgraf (Cyclobios, Austria). Cai (in nmol/l) was calculated according to the ratio in situ calibration technique using ionomycin or digitonin and pHi was determined by calibration with the nigericin/ high potassium technique [16].…”

Section: Stimvastatin Inhibits Transformation By Rasmentioning

confidence: 99%

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Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Fürst

Haller²,

Chwatal³

et al. 2002

Cell Physiol Biochem

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In previous studies we have shown that the expression of the transformingHa-ras oncogene in NIH 3T3 fibroblasts stimulates cellular calcium entry, which triggers oscillatory calcium induced calcium release from internal stores. The intracellular calcium oscillations lead to cytoskeletal remodeling by actin stress fiber depolymerization and activation of the Na⁺/H⁺ exchanger thus mediating cell swelling and intracellular alkalosis, both important mitogenic signals. This is evidenced by abrogation of Ha-ras induced growth factor independent cell proliferation by interference with any of these events, i.e. by inhibition of cellular calcium entry or inhibition of the Na⁺/H⁺ exchanger.As shown in this study, simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis, is able to prevent these events following the expression of the transforming Ha-ras oncogene. We show, that simvastatin inhibits farnesylation dependent membrane translocation of a CAAX motive bearing yellow fluorescent protein and suppresses Ha-ras stimulated cellular calcium influx, which can be identified as capacitative calcium entry. In addition simvastatin is able to block regulatory volume decrease channels and to suppress the cytoskeletal remodeling, intracellular alkalinization, increase in cell volume and growth factor independent cell proliferation induced by the oncogene.Thus simvastatin is able to prevent crucial cellular events following expression of the transforming Ha-ras oncogene.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Stimvastatin Inhibits Transformation By Rasmentioning

confidence: 99%

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Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Fürst

Haller²,

Chwatal³

et al. 2002

Cell Physiol Biochem

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“…For instance, oscillating K þ channel activity in proliferating cells [47,149] differs from the sustained K þ channel activation in apoptotic cells [150]. The short-lived increases in cytosolic Ca 2þ concentration triggered by oscillatory Ca 2þ channel activity depolymerize the cytoskeleton [120,[151][152][153] but are presumably too short to activate caspases [154] or to trigger cell membrane scrambling [155,156]. Moreover, the eventual outcome may depend on the extent of channel activation.…”

Section: Resultsmentioning

confidence: 99%

Ion channels in cancer: future perspectives and clinical potential

Läng

Stournaras

2014

Phil. Trans. R. Soc. B

139

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Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca 2+ permeable channels, K + channels, Na + channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca 2+ permeable channels, K + channels, Na + channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.

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“…The physiological effect of Ras activation is mostly related to proliferation and/or differentiation depending on cell type and physiological state (Marshall, 1995). In this context, Ras activation has been shown to impact on the function of membrane channels or transporters (Houseknecht et al, 1996;Ma et al, 1996;Ritter et al, 1997), and in other cases Ras activation has been shown to lead to an increase in the number of transport proteins that are expressed in terminally differentiated cells (Pollock and Rane, 1996;Yoshikawa et al, 1996). It is conceivable that K-Ras2A plays a similar function in epithelial target cells of aldosterone, acting on the function and expression of Na ϩ channels.…”

Section: Activity Of Surface Enacmentioning

confidence: 99%

Ras Pathway Activates Epithelial Na⁺Channel and Decreases Its Surface Expression inXenopusOocytes

Mastroberardino¹,

Spindler²,

Forster³

et al. 1998

MBoC

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The small G protein K-Ras2A is rapidly induced by aldosterone in A6 epithelia. In these Xenopus sodium reabsorbing cells, aldosterone rapidly activates preexisting epithelial Na+channels (XENaC) via a transcriptionally mediated mechanism. In the Xenopus oocytes expression system, we tested whether the K-Ras2A pathway impacts on XENaC activity by expressing XENaC alone or together withXK-Ras2A rendered constitutively active (XK-Ras2AG12V). As a second control,XENaC-expressing oocytes were treated with progesterone, a sex steroid that induces maturation of the oocytes similarly to activated Ras. Progesterone or XK-Ras2AG12Vled to oocyte maturation characterized by a decrease in surface area and endogenous Na+ pump function. In both conditions, the surface expression of exogenous XENaC′s was also decreased; however, in comparison with progesterone-treated oocytes,XK-ras2AG12V-coinjected oocytes expressed a fivefold higher XENaC-mediated macroscopic Na+ current that was as high as that of control oocytes. Thus, the Na+ current per surface-expressedXENaC was increased byXK-Ras2AG12V. The chemical driving force for Na+ influx was not changed, suggesting thatXK-Ras2AG12V increased the mean activity ofXENaCs at the oocyte surface. These observations raise the possibility that XK-Ras2A, which is the first regulatory protein known to be transcriptionally induced by aldosterone, could play a role in the control of XENaC function in aldosterone target cells.

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Activation of the Na+/H+-exchanger is NIH 3T3 fibroblasts expressing the Ha-ras oncogene requires stimulated calcium influx and is associated with rearrangement of the actin cytoskeleton

Cited by 10 publications

References 0 publications

Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Ion channels in cancer: future perspectives and clinical potential

Ras Pathway Activates Epithelial Na⁺Channel and Decreases Its Surface Expression inXenopusOocytes

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Activation of the Na+/H+-exchanger is NIH 3T3 fibroblasts expressing the Ha-ras oncogene requires stimulated calcium influx and is associated with rearrangement of the actin cytoskeleton

Cited by 10 publications

References 0 publications

Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Simvastatin Inhibits Malignant Transformation Following Expression of the <i>Ha-ras</i> Oncogene in NIH 3T3 Fibroblasts

Ion channels in cancer: future perspectives and clinical potential

Ras Pathway Activates Epithelial Na+Channel and Decreases Its Surface Expression inXenopusOocytes

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Ras Pathway Activates Epithelial Na⁺Channel and Decreases Its Surface Expression inXenopusOocytes