Inhibition of PI3k/Akt/mTOR signaling by natural products

Anti-Cancer Agents in Medicinal Chemistry

Volumn 13, Issue 7, 2013, Pages 967-970

  Huang, Shile ^a,b  

^a Department of Biochemistry and Molecular Biology ^*  (United States)

^b LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOTRIENOL; APIGENIN; CRYPTOTANSHINONE; CURCUMIN; DEGUELIN; FISETIN; GENISTEIN; INDOLE; MAMMALIAN TARGET OF RAPAMYCIN; NUTRACEUTICAL; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; QUERCETIN; RESVERATROL; RHEB PROTEIN;

ANTINEOPLASTIC ACTIVITY; AUTOPHOSPHORYLATION; BLADDER CANCER; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; DOWN REGULATION; DRUG BIOAVAILABILITY; EDITORIAL; HUMAN; KIDNEY CANCER; NEOPLASM; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS INHIBITION; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANIMALS; BIOLOGICAL PRODUCTS; ENZYME INHIBITORS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84882741522     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/1871520611313070001     Document Type: Editorial

References (52)

1. Polak, P.; Hall, M.N. mTOR and the control of whole body metabolism. Curr. Opin. Cell Biol., 2009, 21, 209-218.
2. Strimpakos, A.S.; Karapanagiotou, E.M.; Saif, M.W.; Syrigos, K.N. The role of mTOR in the management of solid tumors: an overview. Cancer Treat. Rev., 2009, 35, 148-159.
3. Laplante, M.; Sabatini, D.M. mTOR Signaling in Growth Control and Disease. Cell, 2012, 149, 274-293.
4. Zhou, H.; Luo, Y.; Huang, S. Updates of mTOR inhibitors. Anticancer Agents Med. Chem., 2010, 10, 571-581.
5. Gao, X.; Zhang, Y.; Arrazola, P.; Hino, O.; Kobayashi, T.; Yeung, R.S.; Ru, B.; Pan, D. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol., 2002, 4, 699-704.
6. Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol., 2002, 4, 648-657.
7. Tee, A.R.; Fingar, D.C.; Manning, B.D.; Kwiatkowski, D.J.; Cantley, L.C.; Blenis, J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 13571-13576.
8. Stocker, H.; Radimerski, T.; Schindelholz, B.; Wittwer, F.; Belawat, P.; Daram, P.; Breuer, S.; Thomas, G.; Hafen, E. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol., 2002, 5, 559-565.
9. Zhang, Y.; Gao, X.; Saucedo, L.J.; Ru, B.; Edgar, B.A.; Pan, D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol., 2003, 5, 578-581.
10. Garami, A.; Zwartkruis, F.J.; Nobukuni, T.; Joaquin, M.; Roccio, M.; Stocker, H.; Kozma, S.C.; Hafen, E.; Bos, J.L.; Thomas, G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell, 2003, 11, 1457-1466.
11. Inoki, K.; Li, Y.; Xu, T.; Guan, K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev., 2003, 17, 1829-1834.
12. Tee, A.R.; Manning, B.D.; Roux, P.P.; Cantley, L.C.; Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol., 2003, 13, 1259-1268.
13. Manning, B.D.; Cantley, L.C. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci., 2003, 28, 573-576.
14. Bai, X.; Ma, D.; Liu, A.; Shen, X.; Wang, Q.J.; Liu, Y.; Jiang, Y. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science, 2007, 318, 977-980.
15. Wang, X.; Fonseca, B.D.; Tang, H.; Liu, R.; Elia, A.; Clemens, M.J.; Bommer, U.A.; Proud, C.G. Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem., 2008, 283, 30482-30492.
16. Sancak, Y.; Peterson, T.R.; Shaul, Y.D.; Lindquist, R.A.; Thoreen, C.C.; Bar-Peled, L.; Sabatini, D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 2008, 320, 1496-1501.
17. Kim, E.; Goraksha-Hicks, P.; Li, L.; Neufeld, T.P.; Guan, K.L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol., 2008, 10, 935-945.
18. Sancak, Y.; Bar-Peled, L.; Zoncu, R.; Markhard, A.L.; Nada, S.; Sabatini, D.M. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 2010, 141, 290-303.
19. Hara, K.; Maruki, Y.; Long, X.; Yoshino, K.; Oshiro, N.; Hidayat, S.; Tokunaga, C.; Avruch, J.; Yonezawa, K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 2002, 110, 177-189.
20. Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.; Erdjument-Bromage, H, Tempst, P.; Sabatini, D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 2002, 110, 163-175.
21. Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; Latek, R.R.; Guntur, K.V.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell, 2003, 11, 895-904.
22. Loewith, R.; Jacinto, E.; Wullschleger, S.; Lorberg, A.; Crespo, J.L.; Bonenfant, D.; Oppliger, W.; Jenoe, P.; Hall, M.N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell, 2002, 10, 457-468.
23. Sancak, Y.; Thoreen, C.C.; Peterson, T.R.; Lindquist, R.A.; Kang, S.A.; Spooner, E.; Carr, S.A.; Sabatini, D.M. PRAS40 is an insulinregulated inhibitor of the mTORC1 protein kinase. Mol. Cell, 2007, 25, 903-915.
24. Vander Haar, E.; Lee, S.I.; Bandhakavi, S.; Griffin, T.J.; Kim, D.H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol., 2007, 9, 316-323.
25. Frias, M.A.; Thoreen, C.C.; Jaffe, J.D.; Schroder, W.; Sculley, T.; Carr, S.A.; Sabatini, D.M. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol., 2006, 16,1865-1870.
26. Jacinto, E.; Loewith, R.; Schmidt, A.; Lin, S.; Ruegg, M.A.; Hall, A.; Hall, M.N. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol., 2004, 6, 1122-1128.
27. Jacinto, E.; Facchinetti, V.; Liu, D.; Soto, N.; Wei, S.; Jung, S.Y.; Huang, Q.; Qin, J.; Su, B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell, 2006, 127, 125-137.
28. Pearce, L.R.; Huang, X.; Boudeau, J.; Pawlowski, R.; Wullschleger, S.; Deak, M.; Ibrahim, A.F.; Gourlay, R.; Magnuson, M.A.; Alessi, D.R. Identification of Protor as a novel Rictorbinding component of mTOR complex-2. Biochem. J., 2007, 405, 513-522.
29. Sarbassov, D.D.; Ali, S.M.; Kim, D.H.; Guertin, D.A.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol., 2004, 14, 1296-1302.
30. Yang, Q.; Inoki, K.; Ikenoue, T.; Guan, K.L. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev., 2006, 20, 2820-2832.
31. Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307, 1098-1101.
32. Woo, S.Y.; Kim, D.H.; Jun, C.B.; Kim, Y.M.; Haar, E.V.; Lee, S.I.; Hegg, J.W.; Bandhakavi, S.; Griffin, T.J.; Kim, D.H. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J. Biol. Chem., 2007, 282, 25604-25612.
33. García-Martínez, J.M.; Alessi, D.R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J., 2008, 416, 375-85.
34. Liu, L.; Chen, L.; Chung, J.; Huang, S. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene, 2008, 27, 4998-5010.
35. Liu, L.; Luo, Y.; Chen, L.; Shen, T.; Xu, B.; Chen, W.; Zhou, H.; Han, X.; Huang, S. Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J. Biol. Chem., 2010, 285, 38362-38373.
36. Haruta, T.; Uno, T.; Kawahara, J.; Takano, A.; Egawa, K.; Sharma, P.M.; Olefsky, J.M.; Kobayashi, M. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol. Endocrinol., 2000, 14, 783-794.
37. Martin, K.A.; Merenick, B.L.; Ding, M.; Fetet-alvero, K.M.; Rzucidlo, E.M.; Kozul, C.D.; Brown, D.J.; Chiu, H.Y.; Shyu, M.; Drapeau, B.L.; Wagner, R.J.; Powell, R.J. Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling. J. Biol. Chem., 2007, 282, 36112-36120.
38. Jung, C.H.; Jun, C.B.; Ro, S.H.; Kim, Y.M.; Otto, N.M.; Cao, J.; Kundu, M.; Kim, D.H. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell, 2009, 20, 1992-2003.
39. Hosokawa, N.; Hara, T.; Kaizuka, T.; Kishi, C.; Takamura, A.; Miura, Y.; Iemura, S.; Natsume, T.; Takehana, K.; Yamada, N.; Guan, J.L.; Oshiro, N.; Mizushima, N. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell, 2009, 20, 1981-1991.
40. Ganley, I.G.; Lam, du H.; Wang, J.; Ding, X.; Chen, S.; Jiang, X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem., 2009, 284, 12297-305.
41. Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 2009, 137, 873-886.
42. Gerlinger, M.; Rowan, A.J.; Horswell, S.; Larkin, J.; Endesfelder, D.; Gronroos, E.; Martinez, P.; Matthews, N.; Stewart, A.; Tarpey, P.; Varela, I.; Phillimore, B.; Begum, S.; McDonald, N.Q.; Butler, A.; Jones, D.; Raine, K.; Latimer, C.; Santos, C.R.; Nohadani, M.; Eklund, A.C.; Spencer-Dene, B.; Clark, G.; Pickering, L.; Stamp, G.; Gore, M.; Szallasi, Z.; Downward, J.; Futreal, P.A.; Swanton, C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med., 2012, 366, 883-892.
43. Tong, X.; Pelling, J. Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention. Anticancer Agents Med. Chem. (This issue)
44. Chen, W.; Lu, Y.; Chen, G.; Huang, S. Molecular evidence of cryptotanshinone for treatment and prevention of human cancer. Anticancer Agents Med. Chem., (This issue)
45. Beevers, C.S.; Huang, S. Hitting the Golden TORget: Curcumin's Effects on mTOR Signaling. Anticancer Agents Med. Chem., (This issue)
46. Syed, D.N.; Adhami, V.M.; Khan, M.I.; Mukhtar, H. Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anticancer Agents Med. Chem., (This issue)
47. Ahmad, A.; Biersack, B.; Li, Y.; Kong, D.; Bao, B.; Schobert, R.; Padhye, S.B.; Sarkar, F.H. Targeted regulation of PI3K/Akt/ mTOR/NF-_B signaling by indole compounds and their derivatives: Mechanistic details and biological implications for cancer therapy. Anticancer Agents Med. Chem., (This issue)
48. Ahmad, A.; Biersack, B.; Li, Y.; Bao, B.; Kong, D.; Schobert, R.; Padhye, S.B.; Sarkar, F.H. Deregulation of PI3K/Akt/mTOR signaling by isoflavones and its implication in cancer research. Anticancer Agents Med. Chem., (This issue)
49. Brüning, A. Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anticancer Agents Med. Chem., (This issue)
50. Wu, Y.; Liu, F. Targeting mTOR: Evaluating the Therapeutic Potential of Resveratrol for Cancer Treatment. Anticancer Agents Med. Chem., (This issue)
51. Sylvester, P.W.; Ayoub, N.M. Tocotrienols target PI3K/Akt signaling in anti-breast cancer therapy. Anticancer Agents Med. Chem., (This issue)
52. Wang, Z.; Sun, H.; Yakisich, J.S. Natural products targeting autophagy via the PI3K/Akt pathway as anticancer agents. Anticancer Agents Med. Chem., (This issue)