The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

Oncotarget

Volumn 7, Issue 20, 2016, Pages 28849-28867

  Campanella, Claudia ^a,b   D'Anneo, Antonella ^a   Gammazza, Antonella Marino ^a,b   Bavisotto, Celeste Caruso ^a,b   Barone, Rosario ^a,b   Emanuele, Sonia ^a   Lo Cascio, Filippa ^a   Mocciaro, Emanuele ^a   Fais, Stefano ^c   De Macario, Everly Conway ^d   Macario, Alberto J L ^b,d   Cappello, Francesco ^a,b   Lauricella, Marianna ^a  

^a UNIVERSITY OF PALERMO   (Italy)

^b Euro Mediterranean Institute of Science and Technology   (Italy)

^c ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^d UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

Exosomes; Histone deacetylase inhibitor; HSP60; Oxidative stress; SAHA

Indexed keywords

CHAPERONIN 60; HISTONE DEACETYLASE INHIBITOR; MESSENGER RNA; REACTIVE OXYGEN METABOLITE; VORINOSTAT; ANTINEOPLASTIC AGENT; HSPD1 PROTEIN, HUMAN; HYDROXAMIC ACID; MITOCHONDRIAL PROTEIN;

ARTICLE; CELL VIABILITY; CONTROLLED STUDY; DRUG CYTOTOXICITY; EXOSOME; G2 PHASE CELL CYCLE CHECKPOINT; HUMAN; HUMAN CELL; LUNG CANCER CELL LINE; MITOCHONDRIAL MEMBRANE POTENTIAL; NITRATION; OXIDATIVE STRESS; PROTEIN PROCESSING; PROTEIN SECRETION; APOPTOSIS; CELL PROLIFERATION; CELL SURVIVAL; DRUG EFFECTS; LUNG TUMOR; METABOLISM; NITROSATION; PATHOLOGY; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CELL PROLIFERATION; CELL SURVIVAL; CHAPERONIN 60; EXOSOMES; HISTONE DEACETYLASE INHIBITORS; HUMANS; HYDROXAMIC ACIDS; LUNG NEOPLASMS; MITOCHONDRIAL PROTEINS; NITROSATION; PROTEIN PROCESSING, POST-TRANSLATIONAL;

EID: 84969895342     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.6680     Document Type: Article

References (97)

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics. 2012. CA Cancer J Clin. 2015;65:87-108. doi: 10.3322/caac.21262.
2. Zhang L, Fok JH, Davies FE. Heat shock proteins in multiple myeloma. Oncotarget. 2014;5:1132-48. doi: 10.18632/oncotarget.1584.
3. Kast RE, Boockvar JA, Brüning A, Cappello F, Chang WW, Cvek B, Dou QP, Duenas-Gonzalez A, Efferth T, Focosi D, Ghaffari SH, Karpel-Massler G, Ketola K, et al. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget. 2013;4:502-30. doi: 10.18632/oncotarget.969.
4. Zhong H, Yang Y, Ma S, Xiu F, Cai, Z, Zhao H, Du L. Induction of a tumour-specific CTL response by exosomes isolated from heat treated malignant ascites of gastric cancer patients. Int J Hyperthermia. 2011;27:604-11. doi: 10.3109/02656736.2011.564598
5. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, Lin HM, Shang CZ, Chen YJ, Min J. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumour responses in vitro. J Biol Chem. 2012;287:15874-85. doi: 10.1074/jbc.M112.340588
6. Azoitei N, Diepold K, Brunner C, Rouhi A, Genze F, Becher A, Kestler H, van Lint J, Chiosis G, Koren J 3rd, Fröhling S, Scholl C, Seufferlein T. HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization. Cancer Res. 2014;74:7125-36. doi: 10.1158/0008-5472.CAN-14-1017
7. Bailey CK, Budina-Kolomets A, Murphy ME, Nefedova Y. Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma. Cancer Biol Ther. 2015;16:1422-26. doi: 10.1080/15384047.2015.1071743
8. Chatterjee M, Andrulis M, Stühmer T, Müller E, Hofmann C, Steinbrunn T, Heimberger T, Schraud H, Kressmann S, Einsele H, Bargou RC. The PI3K/Akt signaling pathway regulates the expression of HSP70, which critically contributes to HSP90-chaperone function and tumor cell survival in multiple myeloma. Haematologica. 2013;98:1132-41. doi: 10.3324/haematol.2012.066175.
9. Chen WS, Chen CC, Chen LL, Lee CC, Huang TS. Secreted heat shock protein 90a (HSP90a) induces nuclear factor-?B-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J Biol Chem. 2013;29;288:9001-10. doi: 10.1074/jbc.M112.437897.
10. Reebye V, Querol Cano L, Lavery DN, Brooke GN, Powell SM, Chotai D, Walker MM, Whitaker HC, Wait R, Hurst HC, Bevan CL. Role of the HSP90-associated cochaperone p23 in enhancing activity of the androgen receptor and significance for prostate cancer. Mol Endocrinol. 2012;26:1694-06.
11. Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK. HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem. 2012;287:10051-59. doi: 10.1074/jbc.M111.335000.
12. Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 2009;14:105-11. doi: 10.1007/s12192-008-0068-7.
13. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144: 646-74. doi: 10.1016/j.cell.2011.02.013.
14. Meehan K, Vella LJ. The contribution of tumour-derived exosomes to the hallmarks of cancer. Crit Rev Clin Lab Sci. 2015;19:1-11.
15. Cappello F, Conway de Macario E, Marasà L, Zummo G, Macario AJL. HSP60 expression, new locations, functions and perspectives for cancer diagnosis and therapy. Cancer Biol Ther. 2008;7:801-09.
16. Rappa F, Farina F, Zummo G, David S, Campanella C, Carini F, Tomasello G, Damiani P, Cappello F, Conway de Macario E, Macario AJL. HSP-molecular chaperones in cancer biogenesis and tumour therapy: an overview. Anticancer Res. 2012;32:5139-50.
17. Cappello F HSP60 and HSP10 as diagnostic and prognostic tools in the management of exocervical carcinoma. Gynecol Oncol. 2003;91:661.
18. Cappello F and Zummo G. HSP60 expression during carcinogenesis: A molecular "Proteus" of carcinogenesis? Cell Stress Chaperones. 2005;10:263-64.
19. Cappello F, Bellafiore M, David S, Anzalone R. and Zummo G. Ten kilodalton heat shock protein (HSP10) is overexpressed during carcinogenesis of large bowel and uterine exocervix. Cancer Lett. 2003;196:35-41.
20. Cappello F, Bellafiore M, Palma A, David S, Marcianò V, Bartolotta T, Sciumè C, Modica G, Farina F, Zummo G. and Bucchieri F. 60kda chaperonin (HSP60) is over-expressed during colorectal carcinogenesis. Eur J Histochem. 2003;47:105-10.
21. Cappello F, Bellafiore M, Palma A, Marcianò V, Martorana G, Belfiore P, Martorana A, Farina F, ZummoG. and Bucchieri F. Expression of 60kDa heat shock protein increases during carcinogenesis in the uterine exocervix. Pathobiology. 2002;70:83-88.
22. Cappello F, Rappa F, David S, Anzalone R. and Zummo G. Immunohistochemical evaluation of PCNA, p53, HSP60, HSP10 and MUC-2 presence and expression in prostate carcinogenesis. Anticancer Res. 2003;23:1325-31.
23. Czarnecka, AM, Campanella C, Zummo G. and Cappello F. Mitochondrial chaperones in cancer: from molecular biology to clinical diagnostics. Cancer Biol. Ther. 2006;5:714-20.
24. Yan FQ, Wang JQ, Tsai YP, Wu KJ. HSP60 overexpression increases the protein levels of the p110a subunit of phosphoinositide 3-kinase and c-Myc. Clin Exp Pharmacol Physiol. 2015;42:1092-97. doi: 10.1111/1440-1681.12457.
25. Li XS, Xu Q, Fu XY, Luo WS. Heat shock protein 60 overexpression is associated with the progression and prognosis in gastric cancer. Plos One. 2014;9:e107507. doi: 10.1371/journal.pone.0107507.
26. Macario AJL, Conway de Macario E. Molecular chaperones: multiple functions, pathologies, and potential applications. Front Biosci. 2007;12:2588-600.
27. Campanella C, Bucchieri F, Merendino A.M, Fucarino A, Burgio G, Corona DF, Barbieri G, David S, Farina F, Zummo G, Conway de Macario E, Macario, AJL, Cappello F. The odyssey of HSP60 from tumour cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal protein-trafficking modalities. Plos One. 2012;7:e42008. doi: 10.1371/journal.pone.0042008.
28. Merendino AM, Bucchieri F, Campanella C, Marcianò V, Ribbene A, David S, Zummo G, Burgio G, Corona DFV, Conway de Macario E, Macario AJL, Cappello F. HSP60 is actively secreted by human tumour cells. Plos One. 2010;5:e9247. doi: 10.1371/journal.pone.0009247.
29. Marx Marks PA, Xu WS. Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem.2009;107:600-08. doi: 10.1002/jcb.22185.
30. Lauricella M, Ciraolo A, Carlisi D, Vento R, Tesoriere G. SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells. Biochimie. 2012;94:287-99. doi: 10.1016/j.biochi.2011.06.031.
31. Chen S, Zhao Y, Gou WF, Zhao S, Takano Y, Zheng HC. The anti-tumour effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) on the aggressive phenotypes of ovarian carcinoma cells. PLOS ONE. 2013;8:e79781. doi: 10.1371/journal.pone.0079781.
32. Butler LM. Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA,Richon VM. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth ofprostate cancer cells in vitro and in vivo. Cancer Res. 2000;60:5165-70.
33. Gaupel, A.C, Begley, T, Tenniswood, M. High throughput screening identifies modulators of histone deacetylase inhibitors. BMC Genomics. 2014;15:528. doi: 10.1186/1471-2164-15-528.
34. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30-39. doi: 10.1172/JCI69738.
35. Huang YC, Huang FI, Mehndiratta S, Lai SC, Liou JP, Yang CR. Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis. Oncotarget. 2015;6:18590-601. doi: 10.18632/oncotarget.4068.
36. Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, Shah B, Sharma S, Chang JC, Melnick AM, Hiebert S, Bhalla KN. Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget. 2014;5:5637-50. doi: 10.18632/oncotarget.2154.
37. Yang Y, Fiskus W, Yong B, Atadja P, Takahashi Y, Pandita TK, Wang HG, Bhalla KN. Acetylated HSP70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. Proc Natl Acad Sci USA. 2013;110:6841-46. doi: 10.1073/pnas.1217692110.
38. Haaland I, Opsahl JA, Berven FS, Reikvam H, Fredly HK, Haugse R, Thiede B, McCormack E, Lain S, Bruserud O, Gjertsen BT. Molecular mechanisms of nutlin-3 involve acetylation of p53, histones and heat shock proteins in acute myeloid leukemia. Mol Cancer. 2014;13:116. doi: 10.1186/1476-4598-13-116.
39. Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 2011;3:166-79.
40. Straus DJ, Hamlin PA, Matasar MJ, Lia Palomba M, Drullinsky PR, Zelenetz AD, Gerecitano JF, Noy A,Hamilton AM, Elstrom R, Wegner B, Wortman K, Cella D. Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation. Br J Haematol. 2015;168:663-70. doi: 10.1111/bjh.13195.
41. Kirschbaum M, Gojo I, Goldberg SL, Bredeson C, Kujawski LA, Yang A, Marks P, Frankel P, Sun X, Tosolini A, Eid JE, Lubiniecki GM, Issa JP. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167:185-93. doi: 10.1111/bjh.13016.
42. Gueugnon F, Cartron PF, Charrier C, Bertrand P, Fonteneau JF, Gregoire M, Blanquart C. New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells. Oncotarget. 2014;5:4504-15. doi: 10.18632/oncotarget.2056.
43. Tu Y, Hershman DL, Bhalla K, Fiskus W, Pellegrino CM, Andreopoulou E, Makower D, Kalinsky K, Fehn K, Fineberg S, Negassa A, Montgomery LL, et al. A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer. Breast Cancer Res Treat. 2014;146:145-52. doi: 10.1007/s10549-014-3008-5.
44. Han JY, Lee SH, Lee GK, Yun T, Lee YJ, Hwang KH, Kim JY, Kim HT.Phase I/II study of gefitinib (Iressa(®)) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2015;75:475-83. doi: 10.1007/s00280-014-2664-9.
45. Sun S, Han Y, Liu J, Fang Y, Tian Y, Zhou J, Ma D, Wu P. Trichostatin A targets the mitochondrial respiratory chain, increasing mitochondrial reactive oxygen species production to trigger apoptosis in human breast cancer cells. Plos One. 2014;9:e91610. doi: 10.1371/journal.pone.0091610.
46. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, Johnstone RW. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci U S A. 2001;98:10833-38.
47. Rosato RR, Almenara JA, Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/ WAF1 1. Cancer Res. 2003;63:3637-45.
48. Sarangi U, Singh MK, Abhijnya KV, Reddy LP, Prasad BS, Pitke VV, Paithankar K, Sreedhar AS. HSP60 chaperonin acts as barrier to pharmacologically induced oxidative stress mediated apoptosis in tumour cells with differential stress response. Drug Target Insights. 2013;7:35-51. doi: 10.4137/DTI.S12513.
49. Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K.Hydroxamic Acid Analogue Histone Deacetylase Inhibitors Attenuate Estrogen Receptor-A Levels and Transcriptional Activity: A Result of Hyperacetylation and Inhibition of Chaperone Function of Heat Shock Protein 90. Clin Cancer Res. 2007;13:4882-90.
50. Radi R. Protein tyrosine nitration: biochemical mechanisms and structural basis of its functional effects. Acc Chem Res. 2013;46:550-59. doi: 10.1021/ar300234c.
51. Campanella C, Caruso Bavisotto C, Marino Gammazza A, Nikolic D, Rappa F, David S, Cappello F, Bucchieri F, Fais, S. Exosomal heat shock proteins as new players in tumour cell-to-cell communication. J Circ Biomark. 2014;3:5. doi: 10.5772/58721.
52. Johnstone RM. Exosomes biological significance: A concise review. Blood Cells Mol Dis. 2006;36:315-21.
53. Cornago M, Garcia-Alberich C, Blasco-Angulo N, Vall-Llaura N, Nager M, Herreros J, Comella JX, Sanchis D, Llovera M. Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe. Cell Death Dis. 2014; 5:e1435. doi: 10.1038/cddis.2014.412.
54. Xu XD, Yang L, Zheng LY, Pan YY, Cao ZF, Zhang ZQ, Zhou QS, Yang B, Cao C. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells. BMC Cancer. 2014;14:373. doi: 10.1186/1471-2407-14-373.
55. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38-51.
56. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26:5541-52.
57. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540-45.
58. Rao R, Fiskus W, Ganguly S, Kambhampati S, Bhalla KN. HDAC inhibitors and chaperone function. Adv Cancer Res. 2012;116:239-62. doi: 10.1016/B978-0-12-394387-3.00007-0.
59. Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH. A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell. 2010;37:355-69. doi: 10.1016/j.molcel.2010.01.001.
60. Gorska M, Marino Gammazza A, Zmijewski M.A, Campanella C, Cappello F, Wasiewicz T, Kuban-Jankowska A, Daca A, Sielicka A, Popowska U, Knap N, Antoniewicz J, Wakabayashi T, et al. Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (HSP60). Plos One. 2013;8:e71135. doi: 10.1371/journal.pone.0071135.
61. Nakajima S, Kato H, Takahashi S, Johno H, Kitamura M. Inhibition of NF-?B by MG132 through ER stressmediated induction of LAP and LIP. FEBS Lett. 2011;585:2249-54. doi: 10.1016/j.febslet.2011.05.047.
62. Cappello F, Caramori G, Campanella C, Vicari C, Gnemmi I, Zanini A, Spanevello A, Capelli A, La Rocca G, Anzalone R, Bucchieri F, D'Anna SE, Ricciardolo FL, Brun P, et al. Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis. PLoS One. 2011;6:e28200. doi: 10.1371/journal.pone.0028200.
63. Koeck T, Corbett JA, Crabb JW, Stuehr DJ, Aulak KS. Glucose-modulated Tyrosine Nitration in Beta-Cells: Targets and Consequences Arch Biochem Biophys. 2009;484:221-31.
64. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
65. Monzani E, Roncone R, Galliano M, Koppenol WH, Casella L. Mechanistic insight into the peroxidase catalysed nitration of tyrosine derivatives by nitrite and hydrogen peroxide. Eur J Biochem. 2004;271:895-906.
66. De Bellis F, Carafa V, Conte M, Rotili D, Petraglia F, Matarese F, Françoijs KJ, Ablain J, Valente S, Castellano R, Goubard A, Collette Y, et al. Contextselective death of acute myeloid leukemia cells triggered by the novel hybrid retinoid-HDAC inhibitor MC2392. Cancer Res. 2014;74:2328-39. doi: 10.1158/0008-5472.CAN-13-2568.
67. Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G, Ngo L, Holmgren A, Jiang X, Marks PA. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2005;102: 673-78.
68. Lillig CH, Holmgren A. Thioredoxin and related molecules from biology to health and disease. Antioxid Redox Signal. 2007;9:25-47.
69. Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, Richon VM. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci USA. 2002;99:11700-05.
70. Abello N, Kerstjens HA, Postma DS, Bischoff R. Protein tyrosine nitration: selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identification of tyrosine-nitrated proteins. J Proteome Res. 2009;8:3222-38. doi: 10.1021/pr900039c.
71. Thomson L. 3-Nitrotyrosine Modified Proteins in Atherosclerosis. Dis Markers. 2015; 2015:708282. doi: 10.1155/2015/708282.
72. Chavarría C, Souza JM. Oxidation and nitration of a-synuclein and their implications in neurodegenerative diseases. Arch Biochem Biophys. 2013;533:25-32. doi: 10.1016/j.abb.2013.02.009.
73. Davis CW, Hawkins BJ, Ramasamy S, Irrinki KM, Cameron BA, Islam K, Daswani VP, Doonan PJ, Manevich Y, Madesh M. Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1-and RIP3-mediated necrosis. Free Radic Biol Med. 2010; 48:306-17. doi: 10.1016/j.freeradbiomed.2009.11.001.
74. Franco MC, Ye Y, Refakis CA, Feldman JL, Stokes AL, Basso M, Melero Fernandez de Mera RM, Sparrow NA, Calingasan NY, Kiaei M, Rhoads TW, Ma TC, Grumet M, Barnes S, et al. Nitration of HSP90 induces cell death. Proc Natl Acad Sci USA. 2012;4:1102-11. doi: 10.1073/pnas.1215177110.
75. Franco MC, Ricart KC, Gonzalez AS, Dennys CN, Nelson PA, Janes MS, Mehl RA, Landar A, Estevez AG. Nitration of HSP90 on tyrosine 33 regulates mitochondrial metabolism. J Biol Chem. 2015;31:19055-66. doi: 10.1074/jbc.M115.663278.
76. Brocchieri L, Karlin S. Conservation among HSP60 sequences in relation to structure, function, and evolution. Protein Sci. 2000;9:476-86.
77. Caruso Bavisotto C, Marino Gammazza A, Rappa F, Fucarino A, Pitruzzella A, David S, Campanella C. Exosomes: can doctors still ignore their existence? Euromediterranean Biomed J. 2013;8:137-39.
78. Øverbye A, Skotland T, Koehler CJ, Thiede B, Seierstad T, Berge V, Sandvig K, Llorente A. Identification of prostate cancer biomarkers in urinary exosomes. Oncotarget. 2015;6:30357-76. doi: 10.18632/oncotarget.4851.
79. Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D'Ilio S, Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin PLoS One. 2014;9:e88193. doi: 10.1371/journal.pone.0088193.
80. Campanella C, Rappa F, Sciumè C, Marino Gammazza A, Barone R, Bucchieri F, David S, Curcurù G, Caruso Bavisotto C, Pitruzzella A, Geraci G, Modica G, Farina F, et al. Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer. 2015;121:3230-39. doi: 10.1002/cncr.29499.
81. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA. Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol. 2013;304:954-65. doi: 10.1152/ajpheart.00835.2012.
82. De Maio A. Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: A form of communication during injury, infection, and cell damage. Cell Stress Chaperones. 2011;16:235-49. doi: 10.1007/s12192-010-0236-4.
83. Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, Keiser N, Santaniello F, Tomasi TB. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol. 2000;165:7017-24.
84. Xiao W, Dong W, Zhang C, Saren G, Geng P, Zhao H, Li Q, Zhu J, Li G, Zhang S, Ye M. Effects of the epigenetic drug MS-275 on the release and function of exosomerelated immune molecules in hepatocellular carcinoma cells. Eur J Med Res. 2013;18:61. doi: 10.1186/2047-783X-18-61.
85. Kasic T, Colombo P, Soldani C, Wang CM, Miranda E, Roncalli M, Bronte V, Viola A. Modulation of human T-cell functions by reactive nitrogen species. Eur J Immunol. 2011;41:1843-49. doi: 10.1002/eji.201040868.
86. Gauba V, Grünewald J, Gorney V, Deaton LM, Kang M, Bursulaya B, Ou W, Lerner RA, Schmedt C, Geierstanger BH, Schultz PG, Ramirez-Montagut T. Loss of CD4 T-celldependent tolerance to proteins with modified amino acids. Proc Natl arch Sci USA. 2011;108:12821-26. doi: 10.1073/pnas.1110042108.
87. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
88. Ghosh JC, Dohi T, Kang BH, Altieri DC. HSP60 regulation of tumour cell apoptosis. J Biol Chem. 2008;283:5188-94.
89. Lianos GD, Alexiou GA, Mangano A, Mangano A, Rausei S, Boni L, Dionigi G, Roukos DH. The role of heat shock proteins in cancer. Cancer Lett. 2015;360:114-18. doi: 10.1016/j.canlet.2015.02.026.
90. Carlisi D, D'Anneo A, Martinez R, Emanuele S, Buttitta G, Di Fiore R, Vento R, Tesoriere G, Lauricella M. The oxygen radicals involved in the toxicity induced by parthenolide in MDA-MB-231 cells. Oncol Rep. 2014;32:167-72. doi: 10.3892/or.2014.3212.
91. Maggio B, Raffa D, Raimondi MV, Cusimano MG, Plescia F, Cascioferro S, Cancemi G, Lauricella M, Carlisi D, Daidone G. Synthesis and antiproliferative activity of new derivatives containing the polycyclic system 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3',4':2,3]azepino[4,5-f]azocine. Eur J Med Chem. 2014;72:1-9. doi: 10.1016/j.ejmech.2013.11.016.
92. D'Anneo A, Carlisi D, Lauricella M, Puleio R, Martinez R, Di Bella S, Di Marco P, Emanuele S, Di Fiore R, Guercio A, Vento R, Tesoriere G. Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer. Cell Death Dis. 2013;4:e891. doi: 10.1038/cddis.2013.415.
93. Barone R, Macaluso F, Catanese P, Marino Gammazza A, Rizzuto L, Marozzi P, Lo Giudice G, Stampone T, Cappello F, Morici G, Zummo G, Farina F, Di Felice V. Endurance exercise and conjugated linoleic acid (CLA) supplementation up-regulate CYP17A1 and stimulate testosterone biosynthesis. Plos One. 2013;8:e79686. doi: 10.1371/journal.pone.0079686.
94. Marino Gammazza A, Bucchieri F, Grimaldi LM, Benigno A, Conway de Macario E, Macario AJL, Zummo G, Cappello F. The molecular anatomy of human HSP60 and its similarity with that of bacterial orthologues and acetylcholine receptor reveal a potential pathogenetic role of anti-chaperonin immunity in myasthenia gravis. Cell Mol Neurobiol. 2012;32:943-47. doi: 10.1007/s10571-011-9789-8.
95. Cappello F, Marino Gammazza A, Zummo L, Conway de Macario E, Macario AJ. Hsp60 and AChR crossreactivity in myasthenia gravis: An update. J Neurol Sci. 2010;292:117-18. doi: 10.1016/j.jns.2010.02.021.
96. Rappa F, Sciume C, Lo Bello M, Bavisotto CC, Marino Gammazza A, Barone R, Campanella C, David S, Carini F, Zarcone F, Rizzuto S, Lena A, Tomasello G, et al. Comparative analysis of Hsp10 and Hsp90 expression in healthy mucosa and adenocarcinoma of the large bowel. Anticancer Res. 2014;34:4153-59.
97. Di Felice V, Serradifalco C, Rizzuto L, De Luca A, Rappa F, Barone R, Di Marco P, Cassata G, Puleio R, Verin L, Motta A, Migliaresi C, Guercio A, et al. Silk fibroin scaffolds enhance cell commitment of adult rat cardiac progenitor cells. J Tissue Eng Regen Med. 2013:E51-E64. doi: 10.1002/term.1739.