Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion.
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 Ca(2+) [Ca(2+)](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 (TGFbeta) 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 Ca(2+)-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 approximately 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.
Amuthan
G
G
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Biswas
G
G
Zhang
S Y
SY
Klein-Szanto
A
A
Vijayasarathy
C
C
Avadhani
N G
NG
D000818:Animals; D002277:Carcinoma / Q000473:pathology; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D008564:Membrane Potentials; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D009132:Muscles / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction
D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C534280:Ctsl protein, rat