Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells

Oncotarget

Volumn 6, Issue 28, 2015, Pages 25466-25483

  Gibellini, Lara ^a   Pinti, Marcello ^a   Bartolomeo, Regina ^a   De Biasi, Sara ^a   Cormio, Antonella ^b   Musicco, Clara ^c   Carnevale, Gianluca ^a   Pecorini, Simone ^a   Nasi, Milena ^a   De Pol, Anto ^a   Cossarizza, Andrea ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^b UNIVERSITY OF BARI   (Italy)

^c CNR   (Italy)

Author keywords

CDDO; CDDO Me; Lon; mitochondria

Indexed keywords

ACONITATE HYDRATASE; BARDOXOLONE; CASPASE 3; CASPASE 9; ENDOPEPTIDASE LA; HYDROGEN PEROXIDE; REACTIVE OXYGEN METABOLITE; SUPEROXIDE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR A; UNCLASSIFIED DRUG; ADENOSINE TRIPHOSPHATE DEPENDENT PROTEINASE; ANTINEOPLASTIC AGENT; DNA BINDING PROTEIN; LONP1 PROTEIN, HUMAN; METHYL 2-CYANO-3,12-DIOXOOLEAN-1,9-DIEN-28-OATE; MITOCHONDRIAL PROTEIN; OLEANOLIC ACID; PROTEINASE INHIBITOR; TFAM PROTEIN, HUMAN;

APOPTOSIS; ARTICLE; CANCER CELL; CARBONYLATION; CELL DEATH; CELL PROLIFERATION; CONTROLLED STUDY; DENSITOMETRY; ENZYME ACTIVITY; FLOW CYTOMETRY; HUMAN; HUMAN CELL; MEMBRANE DEPOLARIZATION; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRION; MOLECULAR DYNAMICS; MORPHOLOGY; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN FUNCTION; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; DOSE RESPONSE; DRUG EFFECTS; ENZYMOLOGY; GENETIC TRANSFECTION; GENETICS; HEP-G2 CELL LINE; MCF-7 CELL LINE; METABOLISM; MITOCHONDRIAL DYNAMICS; NEOPLASMS; OXIDATIVE STRESS; PATHOLOGY; PROTEIN CARBONYLATION; SIGNAL TRANSDUCTION; TIME FACTOR;

ACONITATE HYDRATASE; ANTINEOPLASTIC AGENTS; APOPTOSIS; ATP-DEPENDENT PROTEASES; CELL DEATH; CELL PROLIFERATION; DNA-BINDING PROTEINS; DOSE-RESPONSE RELATIONSHIP, DRUG; HEP G2 CELLS; HUMANS; HYDROGEN PEROXIDE; MCF-7 CELLS; MEMBRANE POTENTIAL, MITOCHONDRIAL; MITOCHONDRIA; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL PROTEINS; NEOPLASMS; OLEANOLIC ACID; OXIDATIVE STRESS; PROTEASE INHIBITORS; PROTEIN CARBONYLATION; SIGNAL TRANSDUCTION; SUPEROXIDES; TIME FACTORS; TRANSCRIPTION FACTORS; TRANSFECTION;

EID: 84944459109     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.4510     Document Type: Article

References (45)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-674.
2. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009; 136:823-837.
3. Bernstein SH, Venkatesh S, Li M, Lee J, Lu B, Hilchey SP, Morse KM, Metcalfe HM, Skalska J, Andreeff M, Brookes PS, Suzuki CK. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood. 2012; 119:3321-3329.
4. Rugarli EI, Langer T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 2012; 31:1336-1349.
5. Lu B, Yadav S, Shah PG, Liu T, Tian B, Pukszta S, Villaluna N, Kutejova E, Newlon CS, Santos JH, Suzuki CK. Roles for the human ATP-dependent Lon protease in mitochondrial DNA maintenance. J Biol Chem. 2007; 282:17363-17374.
6. Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol. 2002; 4:674-680.
7. Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, Bogenhagen DF, Temiakov D, Suzuki CK. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol Cell. 2013; 49:121-132.
8. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007; 129:111-122.
9. Ngo JK, Pomatto LC, Bota DA, Koop AL, Davies KJ. Impairment of lon-induced protection against the accumulation of oxidized proteins in senescent wi-38 fibroblasts. J Gerontol A Biol Sci Med Sci. 2011; 66:1178-1185.
10. Pinti M, Gibellini L, De Biasi S, Nasi M, Roat E, O'Connor JE, Cossarizza A. Functional characterization of the promoter of the human Lon protease gene. Mitochondrion. 2011; 11:200-206.
11. Quiros PM, Espanol Y, Acin-Perez R, Rodriguez F, Barcena C, Watanabe K, Calvo E, Loureiro M, Fernandez- Garcia MS, Fueyo A, Vazquez J, Enriquez JA, Lopez- Otin C. ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep. 2014; 8:542-556.
12. Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab. 2012; 23:125-132.
13. Gibellini L, Pinti M, Boraldi F, Giorgio V, Bernardi P, Bartolomeo R, Nasi M, De Biasi S, Missiroli S, Carnevale G, Losi L, Tesei A, Pinton P, Quaglino D, Cossarizza A. Silencing of mitochondrial Lon protease deeply impairs mitochondrial proteome and function in colon cancer cells. FASEB J. 2014; 28:5122-5135.
14. Cheng CW, Kuo CY, Fan CC, Fang WC, Jiang SS, Lo YK, Wang TY, Kao MC, Lee AY. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 2013; 4:e681.
15. Liu Y, Lan L, Huang K, Wang R, Xu C, Shi Y, Wu X, Wu Z, Zhang J, Chen L, Wang L, Yu X, Zhu H, Lu B. Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer. Oncotarget. 2014; 5:11209-11224.
16. Nie X, Li M, Lu B, Zhang Y, Lan L, Chen L, Lu J. Downregulating overexpressed human Lon in cervical cancer suppresses cell proliferation and bioenergetics. PLoS One. 2013; 8:e81084.
17. Liby KT, Sporn MB. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev. 2012; 64:972-1003.
18. Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M, Ruvolo PP. The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia. 2005; 19:1350-1354.
19. Hyer ML, Shi R, Krajewska M, Meyer C, Lebedeva IV, Fisher PB, Reed JC. Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. Cancer Res. 2008; 68:2927-2933.
20. Brookes PS, Morse K, Ray D, Tompkins A, Young SM, Hilchey S, Salim S, Konopleva M, Andreeff M, Phipps R, Bernstein SH. The triterpenoid 2-cyano-3, 12-dioxooleana- 1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore. Cancer Res. 2007; 67:1793-1802.
21. Ikeda T, Sporn M, Honda T, Gribble GW, Kufe D. The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Res. 2003; 63:5551-5558.
22. Lee S, Tak E, Lee J, Rashid MA, Murphy MP, Ha J, Kim SS. Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation. Cell Res. 2011; 21:817-834.
23. Rhee SG, Yang KS, Kang SW, Woo HA, Chang TS. Controlled elimination of intracellular H(2)O(2): regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification. Antioxid Redox Signal. 2005; 7:619-626.
24. Nystrom T. Role of oxidative carbonylation in protein quality control and senescence. EMBO J. 2005; 24:1311-1317.
25. Gibellini L, Pinti M, Nasi M, De Biasi S, Roat E, Bertoncelli L, Cossarizza A. Interfering with ROS Metabolism in Cancer Cells: The Potential Role of Quercetin. Cancers (Basel). 2010; 2:1288-1311.
26. Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004; 7:97-110.
27. Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood. 2003; 101:4098-4104.
28. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2008; 15:171-182.
29. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J, Huang P. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell. 2006; 10:241-252.
30. Chan DC. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol. 2006; 22:79-99.
31. Sheridan C, Martin SJ. Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion. 2010; 10:640-648.
32. Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol. 2002; 159:931-938.
33. Youle RJ, Karbowski M. Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol. 2005; 6:657-663.
34. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004; 15:5001-5011.
35. Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003; 278:7743-7746.
36. Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol. 2005; 37:822-834.
37. Lee HC, Yin PH, Chi CW, Wei YH. Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence. J Biomed Sci. 2002; 9:517-526.
38. Apostolova N, Gomez-Sucerquia LJ, Moran A, Alvarez A, Blas-Garcia A, Esplugues JV. Enhanced oxidative stress and increased mitochondrial mass during efavirenz-induced apoptosis in human hepatic cells. Br J Pharmacol. 2010; 160:2069-2084.
39. Kluza J, Marchetti P, Gallego MA, Lancel S, Fournier C, Loyens A, Beauvillain JC, Bailly C. Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene. 2004; 23:7018-7030.
40. Quaglino D, Boraldi F, Barbieri D, Croce A, Tiozzo R, Pasquali Ronchetti I. Abnormal phenotype of in vitro dermal fibroblasts from patients with Pseudoxanthoma elasticum (PXE). Biochim Biophys Acta. 2000; 1501:51-62.
41. Dickinson BC, Lin VS, Chang CJ. Preparation and use of MitoPY1 for imaging hydrogen peroxide in mitochondria of live cells. Nat Protoc. 2013; 8:1249-1259.
42. Cossarizza A, Baccarani-Contri M, Kalashnikova G, Franceschi C. A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5', '-tetrachloro-1, 1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem Biophys Res Commun. 1993; 197:40-45.
43. Barbieri D, Abbracchio MP, Salvioli S, Monti D, Cossarizza A, Ceruti S, Brambilla R, Cattabeni F, Jacobson KA, Franceschi C. Apoptosis by 2-chloro- 2'-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells. Neurochem Int. 1998; 32:493-504.
44. Salvioli S, Dobrucki J, Moretti L, Troiano L, Fernandez MG, Pinti M, Pedrazzi J, Franceschi C, Cossarizza A. Mitochondrial heterogeneity during staurosporine- induced apoptosis in HL60 cells: analysis at the single cell and single organelle level. Cytometry. 2000; 40:189-197.
45. De Biasi S, Gibellini L, Cossarizza A. Uncompensated Polychromatic Analysis of Mitochondrial Membrane Potential Using JC-1 and Multilaser Excitation. Curr Protoc Cytom. 2015; 72:7.32.1-7.32.11.