Author(s): Ling X, Xu C, Fan C, Zhong K, Li F, et al.
Anticancer agent FL118 was recently identified in screening of small-molecule inhibitors of human survivin expression. Although FL118 is a camptothecin analogue, its antitumor potency is much superior to other FDA-approved camptothecin analogues (irinotecan and topotecan). The mechanism of action (MOA) underlying the antitumor effects of FL118 remains to be fully elucidated. Here, we report that FL118 activates tumor suppressor p53 as a novel MOA in p53 wild-type cancer cells. Our studies show that this MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a manner largely independent of ATM-dependent DNA damage signaling pathway but dependent on E3-competent Mdm2. FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2-MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2-p53 interactions and moderately increases Mdm2-MdmX interactions, suggesting a change of targeting specificity of Mdm2-MdmX E3 complex from p53 to MdmX, resulting in accelerated MdmX degradation. As a result, p53 ubiquitination by Mdm2-MdmX E3 complex is reduced, which in turn activates p53 signaling. Activation of the p53 pathway by FL118 induces p53-dependent senescence in colorectal cancer cells. However, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis. These two distinct cellular consequences collectively contribute to the potent effects of FL118 to inhibit clonogenic potential of colon cancer cells. This study identifies a potential application of FL118 as an MdmX inhibitor for targeted therapies.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/25512388
Author(s): Briskin DP
Author(s): Brown DG, T Lister, TL May-Dracka
Author(s): Pohlit AM, Souza Lima RB,Frausin G,Rocha e SilvaLF,Pinto Lopes SC, et al.
Author(s): Vasilevich NI, Kombarov RV, Genis DV, Kirpichenok MA
Author(s): Mondal S, Bandyopadhyay S, Ghosh MK, Mukhopadhyay S, Roy S, et al.
Author(s): Wall ME, MC Wani, CE Cook, KH Palmer, AT McPhail, et al.
Author(s): Wani MC, Taylor HL, WallME, Coggon P, McPhail AT, et al.
Author(s): Lu AJ, Zhang ZS, Zheng MY, Zou HJ, Luo XM, et al.
Author(s): Hartwell JL
Author(s): Hartwell JL
Author(s): Perdue RE Jr, Abbott BJ, Hartwell JL
Author(s): Pettit GR, Day JF, Hartwell JL, Wood HB
Author(s): Kessel D
Author(s): Kessel D
Author(s): Bosmann HB
Author(s): Horwitz SB, Chang CK, Grollman AP
Author(s): Horwitz SB, Chang CK, Grollman AP
Author(s): Hsiang YH, Hertzberg R, Hecht S, Liu LF
Author(s): Hsiang YH, Liu LF, Wall ME, Wani MC, Nicholas AW
Author(s): Hsiang YH, LF Liu
Author(s): Pommier Y
Author(s): Pommier Y, Kohlhagen G, Kohn KW,Leteurtre F, Wani MC
Author(s): Zhang ZB, Cheng B, Tse-Dinh YC
Author(s): Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG
Author(s): Cliby WA, Lewis KA, Lilly KK, Kaufmann SH
Author(s): Liu LF, Desai SD, Li TK, Mao Y, Sun M, et al.
Author(s): Gallo RC, Whang-Peng J, Adamson RH
Author(s): Pommier Y, Marchand C
Author(s): Pommier Y, Marchand C
Author(s): Marchand C, Antony S, Kohn KW, Cushman M, Ioanoviciu A, et al.
Author(s): Koster DA, Palle K, Bot ES, Bjornsti MA, Dekker NH
Author(s): Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS
Author(s): Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, et al.
Author(s): ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, et al.
Author(s): Perez-Soler R, Glisson BS, Lee JS, Fossella FV, Murphy WK, et al.
Author(s): Gonzalez EE, Villanueva N, Fra J, Berros JP, Jimenez P, et al.
Author(s): Perez-Soler R, Fossella FV, Glisson BS, Lee JS, Murphy WK, et al.
Author(s): Fleming GF, Kugler JW, Hoffman PC, Ansari R, Bitran JD, et al.
Author(s): Wagner S, Peters O, Fels C, Janssen G, Liebeskind AK, et al.
Author(s): Garcia AA, Roman L, Muderspach L, O'meara A, Facio G, et al.
Author(s): Rose PG, Smrekar M, Haba P, Fusco N, Rodriguez MA
Author(s): Nielsen DL, Brünner N
Author(s): Jameson GS, Hamm JT, Weiss GJ, Alemany C, Anthony S, et al.
Author(s): Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, etal.
Author(s): Patel H, Stoller R, Auber M, Potter D, Cai C
Author(s): Chedid S, Rivera E, Frye DK, Ibrahim N, Esteva F, et al.
Author(s): Baka S, Ranson M, Lorigan P, Danson S, Linton K, et al.
Author(s): Burris HA, Rivkin S, Reynolds R, Harris J, Wax A, et al.
Author(s): Reichardt P, Nielsen OS, Bauer S, Hartmann JT, Schöffski P, etal.
Author(s): Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, et al.
Author(s): Esteva FJ, Rivera E, Cristofanilli M, Valero V, Royce M, et al.
Author(s): Royce ME, Rowinsky EK, Hoff PM, Coyle J, DeJager R, et al.
Author(s): Verschraegen CF, Kudelka AP, Hu W, Vincent M, Kavanagh JJ, et al.
Author(s): Ajani JA, Takimoto C, Becerra CR, Silva A, Baez L, et al.
Author(s): Abou-Alfa GK, Rowinsky EK, Patt YZ, Schwartz GK, Kelsen DP, et al.
Author(s): Ling X, Cao S, Cheng Q, Keefe JT, Rustum YM, et al.
Author(s): Li F
Author(s): Vadlapatla RK, Vadlapudi AD, Pal D
Author(s): Beretta GL, Gatti L, Perego P, Zaffaroni N
Author(s): Lei T, Srinivasan S, Tang Y, Manchanda R, Nagesetti A, et al.
Author(s): Wilson TR, Johnston PG, Longley DB