TY - JOUR
T1 - CACNA2D2-mediated apoptosis in NSCLC cells is associated with alterations of the intracellular calcium signaling and disruption of mitochondria membrane integrity
AU - Carboni, Giovanni L.
AU - Gao, Boning
AU - Nishizaki, Masahiko
AU - Xu, Kai
AU - Minna, John D.
AU - Roth, Jack A.
AU - Ji, Lin
N1 - Funding Information:
The authors would like to thank Karen Ramirez and Wend y Schober-Ditmore for their assistance in FACS analysis, and David McConkey, Leta Nutt, and Abujiang Pataer for discussions on the methodology. This work was partially supported by grants from the National Cancer Institute, the National Institutes of Health SPORE (2P50-CA70907-04); (P01 CA78778-01A1) (JAR); (CA71618) (JDM), a WM Keck Gene Therapy Career Development Grant (LJ), by a grant from the Department of the Army BESCT Lung Cancer Program (DAMD17011068902); by the Swiss National Science Foundation (GLC) and Bernische Krebsliga (GLC); by gifts to the Division of Surgery MD Anderson Cancer Center, from Tenneco and Exxon for the Core Laboratory Facility; by the M. D. Anderson Cancer Center Support Core Grant (CA16672); by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8), and by a sponsored research agreement with Introgen Therapeutics, Inc. (SR93-004-1).
PY - 2003/1/30
Y1 - 2003/1/30
N2 - The CACNA2D2 gene, a new subunit of the Ca2+-channel complex, was identified in the homozygous deletion region of chromosome 3p21.3 in human lung and breast cancers. Expression deficiency of the CACNA2D2 in cancer cells suggests a possible link of it to Ca2+ signaling in the pathogenesis of lung cancer and other cancers. We investigated the effects of overexpression of CACNA2D2 on intracellular Ca2+ contents, mitochondria homeostasis, cell proliferation, and apoptosis by adenoviral vector-mediated wild-type CACNA2D2 gene transfer in 3p21.3-deficient nonsmall cell lung cancer cell lines. Exogenous expression of CACNA2D2 significantly inhibited tumor cell growth compared with the controls. Overexpression of CACNA2D2 induced apoptosis in H1299 (12.5%), H358 (13.7%), H460 (22.3%), and A549 (50.1%) cell lines. Levels of intracellular free Ca2+ were elevated in AdCACNA2D2-transduced cells compared with the controls. Mitochondria membrane depolarization was observed prior to apoptosis in Ad-CACNA2D2 and Adp53-transduced H460 and A549 cells. Release of cyt c into the cytosol, caspase 3 activation, and PARP cleavage were also detected in these cells. Together, these results suggest that one of the pathways in CACNA2D2-induced apoptosis is mediated through disruption of mitochondria membrane integrity, the release of cyt c, and the activation of caspases, a process that is associated with regulation of cytosolic free Ca2+ contents.
AB - The CACNA2D2 gene, a new subunit of the Ca2+-channel complex, was identified in the homozygous deletion region of chromosome 3p21.3 in human lung and breast cancers. Expression deficiency of the CACNA2D2 in cancer cells suggests a possible link of it to Ca2+ signaling in the pathogenesis of lung cancer and other cancers. We investigated the effects of overexpression of CACNA2D2 on intracellular Ca2+ contents, mitochondria homeostasis, cell proliferation, and apoptosis by adenoviral vector-mediated wild-type CACNA2D2 gene transfer in 3p21.3-deficient nonsmall cell lung cancer cell lines. Exogenous expression of CACNA2D2 significantly inhibited tumor cell growth compared with the controls. Overexpression of CACNA2D2 induced apoptosis in H1299 (12.5%), H358 (13.7%), H460 (22.3%), and A549 (50.1%) cell lines. Levels of intracellular free Ca2+ were elevated in AdCACNA2D2-transduced cells compared with the controls. Mitochondria membrane depolarization was observed prior to apoptosis in Ad-CACNA2D2 and Adp53-transduced H460 and A549 cells. Release of cyt c into the cytosol, caspase 3 activation, and PARP cleavage were also detected in these cells. Together, these results suggest that one of the pathways in CACNA2D2-induced apoptosis is mediated through disruption of mitochondria membrane integrity, the release of cyt c, and the activation of caspases, a process that is associated with regulation of cytosolic free Ca2+ contents.
KW - Apoptosis
KW - Calcium channel proteins
KW - Human chromosome 3p21.3
KW - Lung cancer
KW - Tumor suppressor genes
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U2 - 10.1038/sj.onc.1206134
DO - 10.1038/sj.onc.1206134
M3 - Article
C2 - 12555074
AN - SCOPUS:0037473104
SN - 0950-9232
VL - 22
SP - 615
EP - 626
JO - Oncogene
JF - Oncogene
IS - 4
ER -