期刊
EMBO JOURNAL
卷 20, 期 8, 页码 1910-1920出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/20.8.1910
关键词
calcium-dependent PKC; cathepsin L expression; invasive phenotypes; mitochondrial membrane potential; stress signaling
资金
- NCI NIH HHS [R01 CA022762, CA-22762, R37 CA022762] Funding Source: Medline
Recently we showed that partial depletion of mitochondrial DNA (genetic stress) or treatment with mitochondrial-specific inhibitors (metabolic stress) induced a stress signaling that was associated with increased cytoplasmic-free Ca2+ [Ca2+](c). In the present study we show that the mitochondria-to-nucleus stress signaling induces invasive phenotypes in otherwise non-invasive C2C12 myoblasts and human pulmonary carcinoma A549 cells. Tumor-specific markers cathepsin L and transforming growth factor beta (TGF beta) are overexpressed in cells subjected to mitochondrial genetic as well as metabolic stress, C2C12 myoblasts subjected to stress showed 4- to 6-fold higher invasion through reconstituted Matrigel membrane as well as rat tracheal xenotransplants in Scid mice. Activation of Ca2+-dependent protein kinase C (PKC) under both genetic and metabolic stress conditions was associated with increased cathepsin L gene expression, which contributes to increased invasive property of cells. Reverted cells with similar to 70% of control cell mtDNA exhibited marker mRNA contents, cell morphology and invasive property closer to control cells. These results provide insights into a new pathway by which mitochondrial DNA and membrane damage can contribute to tumor progression and metastasis.
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