Abstract
BackgroundT-type Ca2+ channels are often aberrantly expressed in different human cancers and participate in the regulation of cell cycle progression, proliferation and death. Methods: RT-PCR, Q-PCR, western blotting and whole-cell patch-clamp recording were employed to assess the expression of T-type Ca2+ channels in leukemia cell lines. The function of T-type Ca2+ channels in leukemia cell growth and the possible mechanism of the effect of T-type Ca2+ channel antagonists on cell proliferation and apoptosis were examined in T-lymphoma cell lines.ResultsWe show that leukemia cell lines exhibited reduced cell growth when treated with T-type Ca2+ channel inhibitors, mibefradil and NNC-55-0396 in a concentration-dependent manner. Mechanistically, these inhibitors played a dual role on cell viability: (i) blunting proliferation, through a halt in the progression to the G1-S phase; and (ii) promoting cell apoptosis, partially dependent on the endoplasmic reticulum Ca2+ release. In addition, we observed a reduced phosphorylation of ERK1/2 in MOLT-4 cells in response to mibefradil and NNC-55-0396 treatment.ConclusionsThese results indicate that mibefradil and NNC-55-0396 regulate proliferation and apoptosis in T-type Ca2+ channel expressing leukemia cell lines and suggest a potential therapeutic target for leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0171-4) contains supplementary material, which is available to authorized users.
Highlights
Intracellular Ca2+ is a crucial secondary messenger that regulates many cellular processes, such as cell cycle progression, proliferation and apoptosis [1,2,3]
We showed that inhibition of T-type Ca2+ channels with antagonists, mibefradil and NNC-55-0396, led to a decrease in proliferation, and an increase in apoptosis of leukemia cells in vitro, which was preceded by disrupting endoplasmic reticulum (ER) Ca2+ homeostasis
The expression of T-type Ca2+ channels in human leukemia cell lines and Peripheral blood mononuclear cell (PBMC) We first examined the expression of T-type Ca2+ channels in human leukemia cell lines (MOLT-4, Jurkat, Ball, HL-60, NB4, HEL, K-562 and U937) using standard reverse transcriptase PCR (RT-PCR)
Summary
Intracellular Ca2+ is a crucial secondary messenger that regulates many cellular processes, such as cell cycle progression, proliferation and apoptosis [1,2,3]. Increased expression of T-type Ca2+ channels can be detected in tumor samples collected from patients These reports show that pharmacological inhibition by small molecule antagonists or RNAi-mediated downregulation of T-type Ca2+ channels leads to inhibition of cancer cell proliferation and inducing cancer cell apoptosis. Results: We show that leukemia cell lines exhibited reduced cell growth when treated with T-type Ca2+ channel inhibitors, mibefradil and NNC-55-0396 in a concentration-dependent manner. These inhibitors played a dual role on cell viability: (i) blunting proliferation, through a halt in the progression to the G1-S phase; and (ii) promoting cell apoptosis, partially dependent on the endoplasmic reticulum Ca2+ release. Conclusions: These results indicate that mibefradil and NNC-55-0396 regulate proliferation and apoptosis in T-type Ca2+ channel expressing leukemia cell lines and suggest a potential therapeutic target for leukemia
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