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The inhibition of chloride intracellular channel 1 enhances Ca²⁺ and reactive oxygen species signaling in A549 human lung cancer cells.

ABSTRACT: Chloride intracellular channel 1 (CLIC1) is a promising therapeutic target in cancer due to its intrinsic characteristics; it is overexpressed in specific tumor types and its localization changes from cytosolic to surface membrane depending on activities and cell cycle progression. Ca²⁺ and reactive oxygen species (ROS) are critical signaling molecules that modulate diverse cellular functions, including cell death. In this study, we investigated the function of CLIC1 in Ca²⁺ and ROS signaling in A549 human lung cancer cells. Depletion of CLIC1 via shRNAs in A549 cells increased DNA double-strand breaks both under control conditions and under treatment with the putative anticancer agent chelerythrine, accompanied by a concomitant increase in the p-JNK level. CLIC1 knockdown greatly increased basal ROS levels, an effect prevented by BAPTA-AM, an intracellular calcium chelator. Intracellular Ca²⁺ measurements clearly showed that CLIC1 knockdown significantly increased chelerythrine-induced Ca²⁺ signaling as well as the basal Ca²⁺ level in A549 cells compared to these levels in control cells. Suppression of extracellular Ca²⁺ restored the basal Ca²⁺ level in CLIC1-knockdown A549 cells relative to that in control cells, implying that CLIC1 regulates [Ca²⁺]_i through Ca²⁺ entry across the plasma membrane. Consistent with this finding, the L-type Ca²⁺ channel (LTCC) blocker nifedipine reduced the basal Ca²⁺ level in CLIC1 knockdown cells to that in control cells. Taken together, our results demonstrate that CLIC1 knockdown induces an increase in the intracellular Ca²⁺ level via LTCC, which then triggers excessive ROS production and consequent JNK activation. Thus, CLIC1 is a key regulator of Ca²⁺ signaling in the control of cancer cell survival.

SUBMITTER: Lee JR

PROVIDER: S-EPMC6802611 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The inhibition of chloride intracellular channel 1 enhances Ca2+ and reactive oxygen species signaling in A549 human lung cancer cells.

Lee Jae-Rin JR Lee Jong-Yoon JY Kim Hyun-Ji HJ Hahn Myong-Joon MJ Kang Jong-Sun JS Cho Hana H

Experimental & molecular medicine 20190717 7

Chloride intracellular channel 1 (CLIC1) is a promising therapeutic target in cancer due to its intrinsic characteristics; it is overexpressed in specific tumor types and its localization changes from cytosolic to surface membrane depending on activities and cell cycle progression. Ca2+ and reactive oxygen species (ROS) are critical signaling molecules that modulate diverse cellular functions, including cell death. In this study, we investigated the function of CLIC1 in Ca2+</sup ...[more]

PMID: 31316050

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The inhibition of chloride intracellular channel 1 enhances Ca²⁺ and reactive oxygen species signaling in A549 human lung cancer cells.

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The inhibition of chloride intracellular channel 1 enhances Ca<sup>2+</sup> and reactive oxygen species signaling in A549 human lung cancer cells.

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