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Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Oncogene volume 21, pages 7839–7849 (2002)Cite this article

Abstract

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 [Ca2+]c, and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFβ1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-XL 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, TGFβ1 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 [Ca2+]c plays an important role in cancer progression and metastasis.

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Acknowledgements

This research was supported in part by NIH grant CA-22762. We thank members of the Avadhani laboratory for valuable suggestions and criticisms. We also thank Ms Molly Higgins for editorial help.

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Authors and Affiliations

  1. Department of Animal Biology and Mari Lowe Center for Comparative Oncology School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, 19104-6047, PA, USA

    Govindasamy Amuthan, Gopa Biswas, Hindupur K Ananadatheerthavarada, Camasamudram Vijayasarathy, Henry M Shephard & Narayan G Avadhani

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  1. Govindasamy Amuthan
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  2. Gopa Biswas
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  3. Hindupur K Ananadatheerthavarada
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  6. Narayan G Avadhani
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Correspondence to Narayan G Avadhani.

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Amuthan, G., Biswas, G., Ananadatheerthavarada, H. et al. Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21, 7839–7849 (2002). https://doi.org/10.1038/sj.onc.1205983

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