The HIV protease inhibitor nelfinavir down-regulates RET signaling and induces apoptosis in medullary thyroid cancer cells

Journal of Clinical Endocrinology and Metabolism

Volumn 99, Issue 5, 2014, Pages

  Kushchayeva, Yevgeniya ^b   Jensen, Kirk ^a   Recupero, Antony ^a   Costello, John ^a   Patel, Aneeta ^a   Klubo Gwiezdzinska, Joanna ^b   Boyle, Lisa ^c   Burman, Kenneth ^b   Vasko, Vasyl ^a  

^a UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES   (United States)

^b WASHINGTON HOSPITAL CENTER   (United States)

^c GEORGETOWN UNIVERSITY HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE 3; CHLOROQUINE; CYCLIN D1; HEAT SHOCK PROTEIN 90; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LIGHT CHAIN 3BII; MICROTUBULE ASSOCIATED PROTEIN; NELFINAVIR; PROTEIN RET; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; CANCER CELL; CASPASE ASSAY; CELL MEMBRANE DEPOLARIZATION; CELL VIABILITY; CLINICAL ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DNA DAMAGE; DRUG MECHANISM; DRUG POTENTIATION; ENZYME ACTIVATION; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN TISSUE; METABOLIC STRESS; MITOCHONDRIAL MEMBRANE POTENTIAL; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; RET GENE; SIGNAL TRANSDUCTION; WESTERN BLOTTING;

ADULT; AGED; APOPTOSIS; AUTOPHAGY; CARCINOMA, MEDULLARY; CELL LINE, TUMOR; CELL PROLIFERATION; DOWN-REGULATION; ENDOPLASMIC RETICULUM STRESS; FEMALE; HIV PROTEASE INHIBITORS; HSP90 HEAT-SHOCK PROTEINS; HUMANS; MALE; MIDDLE AGED; MUTATION; NELFINAVIR; OXIDATIVE STRESS; PROTO-ONCOGENE PROTEINS C-RET; SIGNAL TRANSDUCTION; THYROID NEOPLASMS;

EID: 84899933025     PISSN: 0021972X     EISSN: 19457197     Source Type: Journal    
DOI: 10.1210/jc.2013-3369     Document Type: Article

References (44)

1. Hyer SL, Newbold K, Harmer C. Familial medullary thyroid cancer: clinical aspects and prognosis. Eur J Surg Oncol. 2005;31:415-419.
2. Cook M, Yu XM, Chen H. Notch in the development of thyroid C-cells and the treatment of medullary thyroid cancer. Am J Transl Res. 2010;2:119-125.
3. Wells SA Jr., Santoro M. Targeting the RET pathway in thyroid cancer. Clin Cancer Res. 2009;15:7119-7123.
4. Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93:682-687.
5. Flavin D. Medullary thyroid carcinoma relapse reversed with dichloroacetate: a case report. Oncol Lett. 2010;1:889-891.
6. Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009;16:367-372.
7. Rodriguez-A ntona C, Pallares J, Montero-Conde C, et al. Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. Endocr Relat Cancer. 2010;17: 7-16.
8. Fas snacht M, Kreissl MC, Weismann D, Allolio B. New targets and therapeutic approaches for endocrine malignancies. Pharmacol Ther. 2009;123:117-141.
9. Wells SA Jr., Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30: 134-141.
10. Rengan R, Mick R, Pryma D, et al.Aphase I trial of theHIVprotease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell lung cancer: a report of toxicities and clinical response. J Thorac Oncol. 2012;7:7 09-715.
11. Pan J, Mott M, Xi B, et al. Phase I study of nelfinavir in liposarcoma. Cancer Chemother Pharmacol. 2012;70:791-799.
12. Brunner TB, Geiger M, Grabenbau er GG, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol. 2008;26:2699-2706.
13. Yang Y, Ikezoe T, Nishioka C, et al. NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines. Br J Cancer. 2006; 95:1653-1662.
14. Pore N Gupta AK Cerniglia GJ et al. Nelfinavir down-regulates hypoxia-inducible factor 1-and VEGF expression and increases tumor oxygenation: implications for radiotherapy Cancer Res. 2006 66 9252-9259.
15. Gills JJ, Lopiccolo J, Tsurutani J, et al. Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and a poptosis in vitro and in vivo. Clin Cancer Res. 2007;13:5183-5194.
16. Shim JS, Rao R, Beebe K, et al. Selective inhibition of HER2-positive breast cancer cells by the HIV protease inhibitor nelfinavir. J Natl Cancer Inst. 2012;104:1576-1590.
17. Gills JJ, Lopiccolo J, Dennis PA. Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 2008;4:107-109.
18. Marsee DK, Venkateswaran A, Tao H, et al. Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. J Biol Chem. 2004;279: 43990-43997.
19. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005;5:761-772.
20. Alfano L, Guida T, Provitera L, et al. RET is a heat shock protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block. J Clin Endocrinol Metab. 2010;95:3552-3557.
21. Carlomagno F, Guida T, Anaga nti S, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004;23:6056-6063.
22. Braga-BasariaM,Hardy E, Gottfried R, Burman KD, SajiM,Ringel MD. 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels. J Clin Endocrinol Metab. 2004;89:2982-2988.
23. Klubo-Gwiezdzinska J, Jensen K, Costello J, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer. 2012;19:447-456.
24. Pai VB, Nahata MC. Nelfinavir mesylate: a protease inhibitor. Ann Pharmacother. 1999;33:325-339.
25. Siegelin MD. Inhibition of the mitochondrial Hsp90 chaperone network: a novel, efficient treatment strategy for cancer Cancer Lett. 2013;333:133-146.
26. Siegelin MD, Dohi T, Raskett CM, et al. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J Clin Invest. 2011;121:1349-1360.
27. Mazumdar M, Adhikary A, Chakraborty S, et al. Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways. Apoptosis. 2013;18 :589-604.
28. Tansey MG, Baloh RH, Milbrandt J, Johnson EM Jr. GFR-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neur on. 2000;25:611-623.
29. Touzet O, Philips A. Resveratrol protects against protease inhibitorinduced reactive oxygen species production, reticulum stress and lipid raft perturbation. AIDS. 2010;24:1437-1447.
30. Ameur N, Lacroix L, Roucan S, et al. Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways. Endocr Relat Cancer. 2009;16:1261-1272.
31. Fukuda Y, Takenaka K, Sparreboom A, et al. Human immunodeficiency virus protease inhibitors interact with ATP binding cassette transporter 4/multidrug resistance protein 4: a basis for unanticipated enhanc ed cytotoxicity. Mol Pharmacol. 2013;84:361-371.
32. Raffi F. [Resistance to protease inhibitors: The role of the MDR gene]. Presse Med. 2000;29:2036-2037.
33. Chandler B , Detsika M, Owen A, et al. Effect of transporter modulation on the emergence of nelfinavir resistance in vitro. Antivir Ther. 2007;12:831-834.
34. Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res. 2013;73:3-7.
35. Thomas S Sharma N Golden EB et al. Preferential killing of triplenegative breast cancer cells in vitro and in vivo when pharmacological aggravators of endoplasmic reticulum stress are combined with autophagy inhibitors Cancer Lett. 2012 325 63-71.
36. Lin CI, Whang EE, Lorch JH, Ruan DT. Autoph agic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer. Surgery. 2012;152:1142-1149.
37. Lopez S, Miro O, Martinez E, et al. Mitochondrial effects of anti-retroviral therapies in asymptomatic patients. Antivir Ther. 2004; 9:47-55.
38. Vincent S, Tourniaire F, El Yazidi CM, et al. Nelfinavir induces necrosis of 3T3F44-2A adipocytes by oxidative stress. J Acquir Immune Defic Syndr. 2004;37:1556-1562.
39. Bruning A, Friese K, Burges A, Mylonas I. Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells. Breast Cancer Res. 2010;12:R45.
40. Kulkarni MV, Franklin DS. N-Myc is a downstream target of RET signaling an d is required for transcriptional regulation of p18(Ink4c) by the transforming mutant RET(C634R). Mol Oncol. 2011;5:24-35.
41. Li W, Miao X, Qi Z, Ze ng W, Liang J, Liang Z. Hepatitis B virus X protein upregulates HSP90-expression via activation of c-Myc in human hepatocarcinoma cell line, HepG2. Virol J. 2010;7:45.
42. Calderwood SK, KhalequeMA,Sawye r DB, Ciocca DR. Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci. 2006;31:164-172.
43. Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem. 2006;281:30299-30304.
44. Zheng HY, Zhang XY, Wang XF, Sun BC. Autophagy enhances the aggressiveness of human colorectal cancer cells and their ability to adap t to apoptotic stimulus. Cancer Biol Med. 2012;9:105-110.