K + Channels and the Intracellular Calcium Signal in Human Melanoma Cell Proliferation

Lepple-Wienhues, Albrecht; Berweck, S.; Böhmig, M.; Leo, Chandra P.; Meyling, B.; Garbe, Claus; Wiederholt, Michael

doi:10.1007/s002329900066

Cited by 89 publications

(61 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A,B), which is in line with findings from Lepple‐Wienhues et al . (1996). Conversely, TRAM‐34 suppressed the FBS‐induced fraction of the [Ca 2+ ] i response to levels observed under FBS‐free conditions, suggesting that changes in SK4 activity are relevant for growth factor‐dependent control of [Ca 2+ ] i homeostasis (Fig.…”

Section: Resultsmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

View full text Add to dashboard Cite

Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Inhibition of K ϩ channels by pharmacological agents has been found to inhibit cell proliferation in normal human lymphocytes (18)(19)(20)(21), human melanoma cells (22,23), small cell lung cancer (24), breast (25), and prostate (26) cancer cells. The role of K ϩ channels in cellular proliferation has been thought to be indirect, by either the possible influence of K ϩ channels on the intracellular Ca 2ϩ concentration (27) or, alternatively, the control of cell volume via K ϩ channels (28).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function

Pei¹,

Wiser²,

Slavin³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

157

124

View full text Add to dashboard Cite

TASK3 gene (Kcnk9) is amplified and overexpressed in several types of human carcinomas. In this report, we demonstrate that a point mutation (G95E) within the consensus K ؉ filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, we provide evidence that TASK3 G95E is a dominant-negative mutation, because coexpression of the wild-type and the mutant TASK3 resulted in inhibition of K ؉ current of wild-type TASK3 and its tumorigenicity in nude mice. These results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.T ASK (TWIK-related acid-sensitive K ϩ channels) channels are members of the two-pore domain family of potassium channels, whose structure consists of two-pore forming regions flanked by four transmembrane domains (1, 2). Like other two-pore domain members, these channels show little time or voltage dependence; thus, they have characteristics of leaky K ϩ channels, generating background currents that contribute to membrane potential and the regulation of cell excitability. The activity of TASK channels is modulated by volatile anesthetics (3, 4), neurotransmitters (5, 6), as well as extracellular pH in the physiological range (7-11). TASK3 is expressed at very low levels among the normal tissues except in the brain, where high levels expression of TASK3 were detected (7-9). The physiological functions of TASK channels are largely unknown, though their roles in the regulation of breathing (12, 13), aldosterone secretion (5) and anesthetic-mediated neuronal activity (14) have been proposed. Recently, we showed that TASK3 is amplified in 10% of breast cancers and is overexpressed at a higher frequency of breast, lung, colon, and metastatic prostate cancers (15), suggesting that TASK3 may play a role in pathogenesis of some human carcinomas.Is the dysregulated expression of TASK3 in tumor cells a consequence of their abnormal growth or is this K ϩ channel involved in promoting tumor growth? To begin to answer this question, we created an inactivating mutation of TASK3. We report here that TASK3 G95E is a dominant-negative mutation that abolishes not only TASK3 K ϩ channel activity but also its oncogenic functions. These results provide molecular basis for developing specific blockers for this K ϩ channel in the treatment of cancer. Materials and MethodsPlasmids and Mutagenesis. The coding region of TASK3 was cloned at BamHI and EcoRI sites of the pLPC retroviral expression vector (15) to generate pLPC-TASK3. Site-directed mutagenesis was performed to change Gly-95 to Glu to create pLPC-TASK3 G95E , by using QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. pTracer-TASK 3 G95E was generated by excising TASK3 G95E from pLPC vector and cloned at KpnI...

show abstract

“…It has been suggested that TEA (Nilius and Wohlrab, 1992;Wang et al, 1992;Pancrazio et al, 1993;Lepple-Wienhues et al, 1996;Skryma et al, 1997) and verapamil (Batra et al, 1991;Yao and Kwan, 1999) inhibit the cancer cell proliferation by suppressing their K ϩ fluxes. In this work, we show that verapamil in micromolar concentrations inhibits LNCaP cell proliferation as well.…”

Section: Discussionmentioning

confidence: 99%

Verapamil Inhibits Proliferation of LNCaP Human Prostate Cancer Cells Influencing K⁺ Channel Gating

et al. 2001

View full text Add to dashboard Cite

show abstract

K + Channels and the Intracellular Calcium Signal in Human Melanoma Cell Proliferation

Cited by 89 publications

References 28 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function

Verapamil Inhibits Proliferation of LNCaP Human Prostate Cancer Cells Influencing K⁺ Channel Gating

Contact Info

Product

Resources

About

K + Channels and the Intracellular Calcium Signal in Human Melanoma Cell Proliferation

Cited by 89 publications

References 28 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

Oncogenic potential of TASK3 (Kcnk9) depends on K+channel function

Verapamil Inhibits Proliferation of LNCaP Human Prostate Cancer Cells Influencing K+ Channel Gating

Contact Info

Product

Resources

About

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function

Verapamil Inhibits Proliferation of LNCaP Human Prostate Cancer Cells Influencing K⁺ Channel Gating