Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress

PLoS ONE

Volumn 4, Issue 9, 2009, Pages

  King, Frank W ^a   Fong, Sylvia ^a   Griffin, Chandi ^a   Shoemaker, Mark ^a   Staub, Rick ^a   Zhang, Yan Ling ^a   Cohen, Isaac ^a   Shtivelman, Emma ^a  

^a Bionovo Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANEMARRHENA ASPHODELOIDES EXTRACT; ANTINEOPLASTIC AGENT; BN 108; CASPASE 4; INITIATION FACTOR 2ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; MTORC1 PROTEIN; PLANT MEDICINAL PRODUCT; SAPONIN DERIVATIVE; TIMOSAPONIN AIII; UNCLASSIFIED DRUG; PLANT EXTRACT; PROTEIN KINASE; SAPONIN; STEROID;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; CONTROLLED STUDY; CYTOTOXICITY; DRUG MECHANISM; DRUG STRUCTURE; ENDOPLASMIC RETICULUM STRESS; GENE EXPRESSION; HUMAN; HUMAN CELL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; ANEMARRHENA; CELL LINE; DRUG SCREENING; ENDOPLASMIC RETICULUM; FLOW CYTOMETRY; GENE EXPRESSION REGULATION; GLYCOSYLATION; METABOLISM; STRUCTURE ACTIVITY RELATION; TUMOR CELL LINE;

ANEMARRHENA ASPHODELOIDES;

ANEMARRHENA; APOPTOSIS; CELL LINE, TRANSFORMED; CELL LINE, TUMOR; DRUG SCREENING ASSAYS, ANTITUMOR; ENDOPLASMIC RETICULUM; FLOW CYTOMETRY; GENE EXPRESSION REGULATION, NEOPLASTIC; GLYCOSYLATION; HUMANS; PLANT EXTRACTS; PROTEIN KINASES; SAPONINS; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 70349645385     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0007283     Document Type: Article

References (43)

1. Kawasaki T, Yamauchi T (1963) Saponins of Timo (Anemarrhenae Rhizoma). Ii. Structure of Timosaponin a-Iii. Chem Pharm Bull (Tokyo) 11: 1221-1224.
2. Saito S, Nagase S, Ichinose K (1994) New steroidal saponins from the rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae). Chem Pharm Bull (Tokyo) 42: 2342-2345.
3. Zhang J, Meng Z, Zhang M, Ma D, Xu S, et al. (1999) Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clin Chim Acta 289: 79-88.
4. Sy LK, Yan SC, Lok CN, Man RY, Che CM (2008) Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells. Cancer Res 68: 10229-10237.
5. Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451-454.
6. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519-529.
7. Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, et al. (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165: 347-356.
8. Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14: 1576-1582.
9. Yorimitsu T, Klionsky DJ (2007) Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3: 160-162.
10. Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78: 217-245.
11. Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5: 726-734.
12. Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115: 2679-2688.
13. Diaz-Troya S, Perez-Perez ME, Florencio FJ, Crespo JL (2008) The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 4: 851-865.
14. Proud CG (2009) mTORC1 signalling and mRNA translation. Biochem Soc Trans 37: 227-231.
15. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6: 729-734.
16. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-168.
17. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122-1128.
18. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296-1302.
19. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, et al. (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7: e38.
20. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, et al. (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284: 8023-8032.
21. Shoemaker M, Hamilton B, Dairkee SH, Cohen I, Campbell MJ (2005) In vitro anticancer activity of twelve Chinese medicinal herbs. Phytother Res 19: 649-651.
22. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, et al. (2002) REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 10: 995-1005.
23. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, et al. (2002) Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 22: 2283-2293.
24. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, et al. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/ TSC2 tumor suppressor complex. Genes Dev 18: 2893-2904.
25. Corradetti MN, Inoki K, Guan KL (2005) The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 280: 9769-9772.
26. Reiling JH, Hafen E (2004) The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18: 2879-2892.
27. Skeen JE, Bhaskar PT, Chen CC, Chen WS, Peng XD, et al. (2006) Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 10: 269-280.
28. Copp J, Manning G, Hunter T (2009) TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69: 1821-1827.
29. Audas TE, Li Y, Liang G, Lu R (2008) A novel protein, Luman/CREB3 recruitment factor, inhibits Luman activation of the unfolded protein response. Mol Cell Biol 28: 3952-3966.
30. Horton JD, Goldstein JL, Brown MS (2002) SREBPs: transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol 67: 491-498.
31. Colgan SM, Tang D, Werstuck GH, Austin RC (2007) Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2. Int J Biochem Cell Biol 39: 1843-1851.
32. Kovacs WJ, Tape KN, Shackelford JE, Wikander TM, Richards MJ, et al. (2008) Peroxisome deficiency causes a complex phenotype due to hepatic SREBP/Insig dysregulation associated with endoplasmic reticulum stress. J Biol Chem.
33. Lee JN, Ye J (2004) Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem 279: 45257-45265.
34. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, et al. (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107: 1263-1273.
35. Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS (2008) Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab 8: 512-521.
36. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, et al. (2002) Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489-500.
37. Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, et al. (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett 514: 122-128.
38. Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, et al. (2003) Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem 278: 20915-20924.
39. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, et al. (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307: 935-939.
40. Li J, Ni M, Lee B, Barron E, Hinton DR, et al. (2008) The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells. Cell Death Differ 15: 1460-1471.
41. Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, et al. (2009) The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res 69: 4415-4423.
42. Harding HP, Zhang Y, Khersonsky S, Marciniak S, Scheuner D, et al. (2005) Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression. Cell Metab 2: 361-371.
43. Carra S, Brunsting JF, Lambert H, Landry J, Kampinga HH (2009) HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{alpha} phosphorylation. J Biol Chem 284: 5523-5532.