| Autor: |
Amuthan G; Department of Animal Biology and Mari Lowe Center for Comparative Oncology School of Veterinary Medicine, University of Pennsylvania 3800 Spruce Street, Philadelphia, PA 19104-6047, USA., Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG |
| Jazyk: |
angličtina |
| Zdroj: |
Oncogene [Oncogene] 2002 Nov 07; Vol. 21 (51), pp. 7839-49. |
| DOI: |
10.1038/sj.onc.1205983 |
| Abstrakt: |
We have investigated mechanisms of mitochondrial stress-induced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca(2+)](c), and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFbeta1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X(L) were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFbeta1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondria-to-nucleus signaling pathway operating through increased [Ca(2+)](c) plays an important role in cancer progression and metastasis. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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