Activation of Mitochondrial ERK Protects Cancer Cells from Death Through Inhibition of the Permeability Transition

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080742

Citations 114

Authors

Andrea Rasola

Marco Sciacovelli

Federica Chiara

Boris Pantic

William S Brusilow

Paolo Bernardi

Affiliations

Soon will be listed here.

Abstract

We studied human cancer cell models in which we detected constitutive activation of ERK. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial permeability transition pore (PTP). PTP desensitization and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced glycogen synthase kinase-3 (GSK-3)-dependent phosphorylation of the pore regulator cyclophilin D, whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization was observed in non-transformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and cyclophilin D, a finding that provides a mechanistic basis for increased resistance to apoptosis of neoplastic cells.

Citing Articles

Distribution of the p66Shc Adaptor Protein Among Mitochondrial and Mitochondria-Associated Membranes Fractions in Normal and Oxidative Stress Conditions.

Lebiedzinska-Arciszewska M, Pakula B, Bonora M, Missiroli S, Potes Y, Jakubek-Olszewska P Int J Mol Sci. 2024; 25(23).

PMID: 39684546 PMC: 11640770. DOI: 10.3390/ijms252312835.

N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.

Coluccino G, Negro A, Filippi A, Bean C, Muraca V, Gissi C Commun Biol. 2024; 7(1):1486.

PMID: 39528709 PMC: 11555324. DOI: 10.1038/s42003-024-07172-8.

The Role of Mitochondrial Permeability Transition in Bone Metabolism, Bone Healing, and Bone Diseases.

Zhu X, Qin Z, Zhou M, Li C, Jing J, Ye W Biomolecules. 2024; 14(10).

PMID: 39456250 PMC: 11506728. DOI: 10.3390/biom14101318.

Cell-free ascites from ovarian cancer patients induces Warburg metabolism and cell proliferation through TGFβ-ERK signaling.

Szeocs D, Vida B, Petovari G, Poliska S, Janka E, Sipos A Geroscience. 2024; 46(4):3581-3597.

PMID: 38196068 PMC: 11226691. DOI: 10.1007/s11357-023-01056-1.

Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?.

Coluccino G, Muraca V, Corazza A, Lippe G Biomolecules. 2023; 13(8).

PMID: 37627330 PMC: 10452829. DOI: 10.3390/biom13081265.

References

Lee H, Bach J, Chae H, Lee S, Joo W, Choi S . Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death. J Neurochem. 2004; 88(3):647-56. DOI: 10.1111/j.1471-4159.2004.02191.x. View

Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N . JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J Biol Chem. 2003; 278(20):17593-6. DOI: 10.1074/jbc.C300076200. View

McCubrey J, Steelman L, Chappell W, Abrams S, Wong E, Chang F . Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2006; 1773(8):1263-84. PMC: 2696318. DOI: 10.1016/j.bbamcr.2006.10.001. View

Aoki H, Kang P, Hampe J, Yoshimura K, Noma T, Matsuzaki M . Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem. 2002; 277(12):10244-50. DOI: 10.1074/jbc.M112355200. View

Monick M, Powers L, Barrett C, Hinde S, Ashare A, Groskreutz D . Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity. J Immunol. 2008; 180(11):7485-96. PMC: 2410094. DOI: 10.4049/jimmunol.180.11.7485. View

Susin S, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A . Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med. 1996; 184(4):1331-41. PMC: 2192812. DOI: 10.1084/jem.184.4.1331. View

Dhanasekaran D, Johnson G . MAPKs: function, regulation, role in cancer and therapeutic targeting. Oncogene. 2007; 26(22):3097-9. DOI: 10.1038/sj.onc.1210395. View

Dhillon A, Hagan S, Rath O, Kolch W . MAP kinase signalling pathways in cancer. Oncogene. 2007; 26(22):3279-90. DOI: 10.1038/sj.onc.1210421. View

Chiara F, Castellaro D, Marin O, Petronilli V, Brusilow W, Juhaszova M . Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS One. 2008; 3(3):e1852. PMC: 2267038. DOI: 10.1371/journal.pone.0001852. View

10.

Zhu J, Guo F, Shelburne J, Watkins S, Chu C . Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol. 2003; 13(4):473-81. PMC: 1911206. DOI: 10.1111/j.1750-3639.2003.tb00478.x. View

11.

Yung H, Wyttenbach A, Tolkovsky A . Aggravation of necrotic death of glucose-deprived cells by the MEK1 inhibitors U0126 and PD184161 through depletion of ATP. Biochem Pharmacol. 2004; 68(2):351-60. DOI: 10.1016/j.bcp.2004.03.030. View

12.

Milanesi E, Costantini P, Gambalunga A, Colonna R, Petronilli V, Cabrelle A . The mitochondrial effects of small organic ligands of BCL-2: sensitization of BCL-2-overexpressing cells to apoptosis by a pyrimidine-2,4,6-trione derivative. J Biol Chem. 2006; 281(15):10066-72. DOI: 10.1074/jbc.M513708200. View

13.

Webber M, Bello D, Kleinman H, Hoffman M . Acinar differentiation by non-malignant immortalized human prostatic epithelial cells and its loss by malignant cells. Carcinogenesis. 1997; 18(6):1225-31. DOI: 10.1093/carcin/18.6.1225. View

14.

Juhaszova M, Zorov D, Kim S, Pepe S, Fu Q, Fishbein K . Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004; 113(11):1535-49. PMC: 419483. DOI: 10.1172/JCI19906. View

15.

Hanawa N, Shinohara M, Saberi B, Gaarde W, Han D, Kaplowitz N . Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem. 2008; 283(20):13565-77. PMC: 2376214. DOI: 10.1074/jbc.M708916200. View

16.

Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K . Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection. J Mol Cell Cardiol. 2007; 43(5):564-70. DOI: 10.1016/j.yjmcc.2007.08.010. View

17.

Gramaglia D, Gentile A, Battaglia M, Ranzato L, Petronilli V, Fassetta M . Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-X(L)- and PKB/AKT-independent fashion. Cell Death Differ. 2004; 11(3):342-53. DOI: 10.1038/sj.cdd.4401326. View

18.

Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F . The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem. 2001; 276(15):12030-4. DOI: 10.1074/jbc.M010604200. View

19.

Jope R, Johnson G . The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004; 29(2):95-102. DOI: 10.1016/j.tibs.2003.12.004. View

20.

Rasola A, Geuna M . A flow cytometry assay simultaneously detects independent apoptotic parameters. Cytometry. 2001; 45(2):151-7. DOI: 10.1002/1097-0320(20011001)45:2<151::aid-cyto1157>3.0.co;2-i. View