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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References
Addya S, Anandatheerthavarada HK, Biswas G, Bhagwat SV, Mullick J, Avadhani NG . 1997 J. Cell Biol. 139: 589–599
Amuthan G, Biswas G, Zhang SY, Klein-Szanto A, Vijayasarathy C, Avadhani NG . 2001 EMBO J. 20: 1910–1920
Arnould T, Vankoningsloo S, Renard P, Houbion A, Ninane N, Demazy C, Remacle J, Raes M . 2002 EMBO J. 21: 53–63
Andreyev A, Fiskum G . 1999 Cell Death Differ. 6: 825–832
Babcock DF, Herrington J, Goodwin PC, Park YB, Hille B . 1997 J. Cell Biol. 136: 833–844
Berridge MJ . 1993 Nature 361: 315–325
Biswas G, Adebanjo OA, Freedman BD, Anandatheerthavarada HK, Vijayasarathy C, Zaidi M, Kotlikoff M, Avadhani NG . 1999 EMBO J. 18: 522–533
Buckman JF, Hernandez H, Kress GJ, Votyakova TV, Pal S, Reynolds IJ . 2001 J. Neurosci. Meth. 104: 165–176
Cavalli LR, Liang BC . 1998 Mutat. Res. 398: 19–26
Cavalli LR, Varella-Garcia M, Liang BC . 1997 Cell Growth Differ. 8: 1189–1198
Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159
Cuvier C, Jang A, Hill RP . 1997 Clin. Exp. Metastasis 15: 19–25
Desjardins P, Frost E, Morais R . 1985 Mol. Cell. Biol. 5: 1163–1169
Dey R, Moraes CT . 2000 J. Biol. Chem. 275: 7087–7094
Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, Sidransky D . 2000 Science 287: 2017–2019
Fujimoto K, Sheng H, Shao J, Beauchamp RD . 2001 Exp. Cell Res. 266: 239–249
Giguere L, Morais R . 1981 Somatic Cell Genet. 7: 457–471
Gutierrez AA, Arias JM, Garcia L, Mas-Oliva J, Guerrero-Hernandez A . 1999 J. Physiol. 517: 95–107
Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP . 1995 Cell 82: 415–424
Hansford RG . 1994 J. Bioenerg. Biomembr. 26: 495–508
Hata A . 2001 Exp. Cell Res. 264: 111–116
Hehl S, Golard A, Hille B . 1996 Cell Calcium 20: 515–524
Hofer AM, Curci S, Doble MA, Brown EM, Soybel DI . 2000 Nat. Cell Biol. 2: 392–398
Hofhaus G, Gattermann N . 1999 Biol. Chem. 380: 871–877
Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M . 1999 Nature 397: 530–534
Horton TM, Petros JA, Heddi A, Shoffner J, Kaufman AE, Graham SDJ, Gramlich T, Wallace DC . 1996 Genes Chromosomes Cancer 15: 95–101
Howell AN, Sager R . 1978 Proc. Natl. Acad. Sci. USA 75: 2358–2362
Ichas F, Jouaville LS, Sidash SS, Mazat JP, Holmuhamedov EL . 1994 FEBS Lett. 348: 211–215
Israel BA, Schaeffer WI . 1987 In Vitro Cell. Dev. Biol. 23: 627–632
Israel BA, Schaeffer WI . 1988 In Vitro Cell. Dev. Biol. 24: 487–490
Iwakura T, Fujimoto S, Kagimoto S, Inada A, Kubota A, Someya Y, Ihara Y, Yamada Y, Seino Y . 2000 Biochem. Biophys. Res. Commun. 271: 422–428
Jiang S, Cai J, Wallace DC, Jones DP . 1999 J. Biol. Chem. 274: 29905–29911
Jonasson J, Povey S, Harris H . 1977 J. Cell Sci. 24: 217–254
Jones CT, Ashton IK . 1976 Arch. Biochem. Biophys. 174: 506–522
Jouaville LS, Ichas F, Holmuhamedov EL, Camacho P, Lechleiter JD . 1995 Nature 377: 438–441
King MP, Attardi G . 1989 Science 246: 500–503
Kim K, Cai J, Shuja S, Kuo T, Murnane MJ . 1998 Int. J. Cancer 79: 324–333
Liao X, Butow RA . 1993 Cell 72: 61–71
Luo Y, Bond JD, Ingram VM . 1997 Proc. Natl. Acad. Sci. USA 94: 9705–9710
Missiaen L, Robberecht W, van der Bosch L, Callewaert G, Parys JB, Wuytack F, Raeymaekers L, Nilius B, Eggemont J, Smedt H . 2000 Cell Calcium 28: 1–21
Mira N, Joshi MD, Jagannathan V . 1967 Meth. Enzymol. 9: 371–373
Miranda S, Foncea R, Guerrero J, Leighton F . 1999 Biochem. Biophys. Res. Commun. 258: 44–49
Mooradian DL, McCarthy JB, Komanduri KV, Furcht LT . 1992 J. Natl. Cancer Ins. 84: 523–527
Morais R, Zinkewich-Peotti K, Parent M, Wang H, Babai F, Zollinger M . 1994 Cancer Res. 54: 3889–3896
Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T . 2000 Mol. Cell. Biol. 20: 7311–7318
Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B . 1998 Nat. Genet. 20: 291–293
Riccardi D . 1999 Cell Calcium 26: 77–83
Richter C . 1993 FEBS Lett. 325: 104–107
Rizzuto R, Brini M, Murgia M, Pozzan T . 1993 Science 262: 744–747
Rothermel BA, Shyjan AW, Etheredge JL, Butow RA . 1995 J. Biol. Chem. 270: 29476–29482
Sheahan K, Shuja S, Murnane MJ . 1989 Cancer Res. 49: 3809–3814
Smith L . 1955 Methods of Biochemical Analysis. Glick D (ed) New York: John Wiley & Sons pp 427–434
Stridh H, Gigliotti D, Orrenius S, Cotgreave I . 1999 Biochem. Biophys. Res. Commun. 266: 460–465
Szalai G, Krishnamurthy R, Hajnoczky G . 1999 EMBO J. 18: 6349–6361
Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB . 2001 Mol. Cell. Biol. 21: 5899–5912
Warburg O, Wind F, Negelein E . 1926 Klin. Woch. 5: 829–832
Warburg O . 1956 Science 123: 309–314
Wen HC, Lin WW . 2000 J. Cell. Biochem. 79: 601–609
Werth JL, Usachev YM, Thayer SA . 1996 J. Neurosci. 16: 1008–1015
Yagel S, Warner AH, Nellans HN, Lala PK, Waghorne C, Denhardt DT . 1989 Cancer Res. 49: 3553–3557
Yeh JJ, Lunetta KL, van Orsouw NJ, Moore FDJ, Mutter GL, Vijg J, Dahia PL, Eng C . 2000 Oncogene 19: 2060–2066
Zafar MN, O'Brien M, Catovsky D . 1982 J. Ultrastruct. Res. 81: 133–138
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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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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DOI: https://doi.org/10.1038/sj.onc.1205983
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