Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells

Oncotarget

Volumn 5, Issue 15, 2014, Pages 6087-6101

  Lee, Yue Zhi ^a   Yang, Cheng Wei ^a   Chang, Hsin Yu ^a   Hsu, Hsing Yu ^a   Chen, Ih Shen ^b   Chang, Hsun Shuo ^b   Lee, Chih Hao ^c   Lee, Jinq chyi ^a   Kumar, Chidambaram Ramesh ^a   Qiu, Ya Qi ^a,d   Chao, Yu Sheng ^a   Lee, Shiow Ju ^a  

^a NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

^b KAOHSIUNG MEDICAL UNIVERSITY   (Taiwan)

^c HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^d NATIONAL TSING HUA UNIVERSITY   (Taiwan)

Author keywords

AMPK; Autophagy; Glutaminase; MTOR; Raptor; ULK1

Indexed keywords

AMINO ACID; BENZOQUINONE DERIVATIVE; ENZYME INHIBITOR; GLUTAMIC ACID; GLUTAMINASE; GLUTAMINASE 2; GLUTAMINASE 2 INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; TARGET OF RAPAMYCIN KINASE;

A549 CELL LINE; ALLOSTERISM; ARTICLE; AUTOPHAGY; BINDING SITE; CANCER CELL CULTURE; CANCER INHIBITION; CARCINOMA CELL; CARCINOMA CELL LINE; CELL PROLIFERATION; COLONY FORMATION; DRUG SCREENING; DRUG SELECTIVITY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME KINETICS; ENZYME PURIFICATION; GENE SILENCING; GLS1 GENE; GLS2 GENE; HEPG2 CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; MOLECULAR CLONING; MOLECULAR DOCKING; PROTEIN EXPRESSION; SITE DIRECTED MUTAGENESIS; STRUCTURE ACTIVITY RELATION; WESTERN BLOTTING; ANTAGONISTS AND INHIBITORS; BREAST TUMOR; DRUG EFFECTS; FEMALE; MCF 7 CELL LINE; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; TUMOR CELL LINE;

AUTOPHAGY; BREAST NEOPLASMS; CELL LINE, TUMOR; CELL PROLIFERATION; FEMALE; GLUTAMINASE; HUMANS; MCF-7 CELLS; MOLECULAR TARGETED THERAPY; MULTIPROTEIN COMPLEXES; TOR SERINE-THREONINE KINASES;

EID: 84906270661     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.2173     Document Type: Article

References (44)

1. Erickson JW and Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget. 2010; 1(8):734-740.
2. Thangavelu K, Pan CQ, Karlberg T, Balaji G, Uttamchandani M, Suresh V, Schuler H, Low BC and Sivaraman J. Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(20):7705-7710.
3. DeLaBarre B, Gross S, Fang C, Gao Y, Jha A, Jiang F, Song JJ, Wei W and Hurov JB. Full-length human glutaminase in complex with an allosteric inhibitor. Biochemistry. 2011; 50(50):10764-10770.
4. Katt WP, Ramachandran S, Erickson JW and Cerione RA. Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation. Molecular cancer therapeutics. 2012; 11(6):1269-1278.
5. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell metabolism. 2012; 15(1):110-121.
6. Shukla K, Ferraris DV, Thomas AG, Stathis M, Duvall B, Delahanty G, Alt J, Rais R, Rojas C, Gao P, Xiang Y, Dang CV, Slusher BS and Tsukamoto T. Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) analogs as glutaminase inhibitors. Journal of medicinal chemistry. 2012; 55(23):10551-10563.
7. Mates JM, Segura JA, Martin-Rufian M, Campos-Sandoval JA, Alonso FJ and Marquez J. Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. Current molecular medicine. 2013; 13(4):514-534.
8. Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, Pereira HM, Garratt RC, Dias SM and Ambrosio AL. Mitochondrial localization and structurebased phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(4):1092-1097.
9. Kvamme E and Torgner IA. Regulatory effects of fatty acyl-coenzyme A derivatives on phosphate-activated pig brain and kidney glutaminase in vitro. The Biochemical journal. 1975; 149(1):83-91.
10. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV and Cerione RA. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer cell. 2010; 18(3):207-219.
11. Hu W, Zhang C, Wu R, Sun Y, Levine A and Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(16):7455-7460.
12. Giacobbe A, Bongiorno-Borbone L, Bernassola F, Terrinoni A, Markert EK, Levine AJ, Feng Z, Agostini M, Zolla L, Agro AF, Notterman DA, Melino G and Peschiaroli A. p63 regulates glutaminase 2 expression. Cell cycle 2013; 12(9):1395-1405.
13. Velletri T, Romeo F, Tucci P, Peschiaroli A, Annicchiarico-Petruzzelli M, Niklison-Chirou MV, Amelio I, Knight RA, Mak TW, Melino G and Agostini M. GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation. Cell cycle 2013; 12(22):3564-3573.
14. Szeliga M, Zgrzywa A, Obara-Michlewska M and Albrecht J. Transfection of a human glioblastoma cell line with liver-type glutaminase (LGA) down-regulates the expression of DNA-repair gene MGMT and sensitizes the cells to alkylating agents. Journal of neurochemistry. 2012; 123(3):428-436.
15. Xiang L, Xie G, Liu C, Zhou J, Chen J, Yu S, Li J, Pang X, Shi H and Liang H. Knock-down of glutaminase 2 expression decreases glutathione, NADH, and sensitizes cervical cancer to ionizing radiation. Biochimica et biophysica acta. 2013; 1833(12):2996-3005.
16. Kim J, Kundu M, Viollet B and Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature cell biology. 2011; 13(2):132-141.
17. Young MM, Kester M and Wang HG. Sphingolipids: regulators of crosstalk between apoptosis and autophagy. Journal of lipid research. 2013; 54(1):5-19.
18. Leontieva OV and Blagosklonny MV. M(o)TOR of pseudohypoxic state in aging: rapamycin to the rescue. Cell cycle 2014; 13(4):509-515.
19. Leontieva OV and Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging. 2011; 3(11):1078-1091.
20. Duran RV and Hall MN. Glutaminolysis feeds mTORC1. Cell cycle 2012; 11(22):4107-4108.
21. Roach PJ. AMPK → ULK1 → autophagy. Molecular and cellular biology. 2011; 31(15):3082-3084.
22. Kang R, Zeh HJ, Lotze MT and Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell death and differentiation. 2011; 18(4):571-580.
23. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A and Guan KL. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature cell biology. 2013; 15(7):741-750.
24. Harvey AL. Natural products in drug discovery. Drug discovery today. 2008; 13(19-20):894-901.
25. Newman DJ and Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of natural products. 2012; 75(3):311-335.
26. Snodgrass PJ and Lund P. Allosteric properties of phosphate-activated glutaminase of human liver mitochondria. Biochimica et biophysica acta. 1984; 798(1):21-27.
27. Chang HS, Lin YJ, Lee SJ, Yang CW, Lin WY, Tsai IL and Chen IS. Cytotoxic alkyl benzoquinones and alkyl phenols from Ardisia virens. Phytochemistry. 2009; 70(17-18):2064-2071.
28. Su TJ, Chang HS, Peng CF, Lee SJ and Chen IS. Antitubercular Resorcinols and Cytotoxic Alkyl Benzoquinones from Ardisia kusukuensis. Taiwan Pharmaceutical Journal 2009; 61:89-105.
29. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Proliferat. 2012; 45(6):487-498.
30. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y and Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. Journal of cell science. 2004; 117(Pt 13):2805-2812.
31. Allan LA and Clarke PR. Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation. The FEBS journal. 2009; 276(21):6063-6073.
32. Peterson RT, Beal PA, Comb MJ and Schreiber SL. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. The Journal of biological chemistry. 2000; 275(10):7416-7423.
33. Huang S and Houghton PJ. Targeting mTOR signaling for cancer therapy. Current opinion in pharmacology. 2003; 3(4):371-377.
34. Cheng SW, Fryer LG, Carling D and Shepherd PR. Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. The Journal of biological chemistry. 2004; 279(16):15719-15722.
35. Manning BD, Tee AR, Logsdon MN, Blenis J and Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Molecular cell. 2002; 10(1):151-162.
36. Inoki K, Zhu T and Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003; 115(5):577-590.
37. Elgadi KM, Meguid RA, Qian M, Souba WW and Abcouwer SF. Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiological genomics. 1999; 1(2):51-62.
38. Gomez-Fabre PM, Aledo JC, Del Castillo-Olivares A, Alonso FJ, Nunez De Castro I, Campos JA and Marquez J. Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase. The Biochemical journal. 2000; 345 Pt 2:365-375.
39. Holcomb T, Taylor L, Trohkimoinen J and Curthoys NP. Isolation, characterization and expression of a human brain mitochondrial glutaminase cDNA. Brain research Molecular brain research. 2000; 76(1):56-63.
40. Yang CW, Yang YN, Liang PH, Chen CM, Chen WL, Chang HY, Chao YS and Lee SJ. Novel smallmolecule inhibitors of transmissible gastroenteritis virus. Antimicrobial agents and chemotherapy. 2007; 51(11):3924-3931.
41. Newcomb RW. (2002). United States Patent No. 6,451, 828 B1. Selective Inhibition of Glutaminase by Bis_ thiadiazoles.
42. Kenny J, Bao Y, Hamm B, Taylor L, Toth A, Wagers B and Curthoys NP. Bacterial expression, purification, and characterization of rat kidney-type mitochondrial glutaminase. Protein expression and purification. 2003; 31(1):140-148.
43. Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, Hansen JC and Curthoys NP. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). The Biochemical journal. 2007; 406(3):407-414.
44. Wu CM, Yang CW, Lee YZ, Chuang TH, Wu PL, Chao YS and Lee SJ. Tylophorine arrests carcinoma cells at G1 phase by downregulating cyclin A2 expression. Biochemical and biophysical research communications. 2009; 386(1):140-145.