ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells.

TitleATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsSong S, Jacobson KN, McDermott KM, Reddy SP, Cress AE, Tang H, Dudek SM, Black SM, Garcia JGN, Makino A, Yuan JX-J
JournalAm J Physiol Cell Physiol
Volume310
Issue2
PaginationC99-114
Date Published2016 Jan 15
ISSN Number1522-1563
KeywordsAdenosine Triphosphate, bcl-2-Associated X Protein, Calcium, Calcium Signaling, Cell Line, Tumor, Cell Survival, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Proto-Oncogene Proteins c-bcl-2
Abstract

<p>Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca(2+) signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca(2+)] ([Ca(2+)]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca(2+) eliminated the plateau phase increase of [Ca(2+)]cyt in lung cancer cells, indicating that the plateau phase of [Ca(2+)]cyt increase is due to Ca(2+) influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca(2+) or chelating intracellular Ca(2+) with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca(2+)]cyt through Ca(2+) influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.</p>

DOI10.1152/ajpcell.00092.2015
Alternate JournalAm. J. Physiol., Cell Physiol.
PubMed ID26491047
PubMed Central IDPMC4719033
Grant ListHL-066012 / HL / NHLBI NIH HHS / United States
R01 HL115014 / HL / NHLBI NIH HHS / United States
R01 HL067841 / HL / NHLBI NIH HHS / United States
HL-115014 / HL / NHLBI NIH HHS / United States
R01 HL066012 / HL / NHLBI NIH HHS / United States
HL-098053 / HL / NHLBI NIH HHS / United States
R01 HL060190 / HL / NHLBI NIH HHS / United States