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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin

Authors: Quan Wang, Feng Wei, Guoyue Lv, Chunsheng Li, Tongjun Liu, Costas G Hadjipanayis, Guikai Zhang, Chunhai Hao, Anita C Bellail

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

There is growing evidence indicating the insulin-like growth factor 1 receptor (IGF-1R) plays a critical role in the progression of human colorectal carcinomas. IGF-1R is an attractive drug target for the treatment of colon cancer. Picropodophyllin (PPP), of the cyclolignan family, has recently been identified as an IGF-1R inhibitor. The aim of this study is to determine the therapeutic response and mechanism after colorectal carcinoma treatment with PPP.

Methods

Seven colorectal carcinoma cell lines were treated with PPP. Following treatment, cells were analyzed for growth by a cell viability assay, sub-G1 apoptosis by flow cytometry, caspase cleavage and activation of AKT and extracellular signal-regulated kinase (ERK) by western blot analysis. To examine the in vivo therapeutic efficacy of PPP, mice implanted with human colorectal carcinoma xenografts underwent PPP treatment.

Results

PPP treatment blocked the phosphorylation of IGF-1R, AKT and ERK and inhibited the growth of TP53 wild-type but not mutated colorectal carcinoma cell lines. The treatment of PPP also induced apoptosis in TP53 wild-type cells as evident by the presence of sub-G1 cells and the cleavage of caspase-9, caspase-3, DNA fragmentation factor-45 (DFF45), poly (ADP-ribose) polymerase (PARP), and X-linked inhibitor of apoptosis protein (XIAP). The loss of BAD phosphorylation in the PPP-treated TP53 wild type cells further suggested that the treatment induced apoptosis through the BAD-mediated mitochondrial pathway. In contrast, PPP treatment failed to induce the phosphorylation of AKT and ERK and caspase cleavage in TP53 mutated colorectal carcinoma cell lines. Finally, PPP treatment suppressed the growth of xenografts derived from TP53 wild type but not mutated colorectal carcinoma cells.

Conclusions

We report the association of TP53 mutations with the resistance of treatment of colorectal carcinoma cells in culture and in a xenograft mouse model with the IGF-1R inhibitor PPP. TP53 mutations often occur in colorectal carcinomas and could be used as a biomarker to predict the resistance of colorectal carcinomas to the treatment by this IGF-1R inhibitor.
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Literature
1.
Pollak M: The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012, 12 (3): 159-169.PubMed
2.
LeRoith D: Insulin-like growth factor I receptor signaling–overlapping or redundant pathways?. Endocrinology. 2000, 141 (4): 1287-1288. 10.1210/en.141.4.1287.PubMed
3.
Petley T, Graff K, Jiang W, Yang H, Florini J: Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Horm Metab Res. 1999, 31 (2–3): 70-76.CrossRefPubMed
4.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ: Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 1996, 87 (4): 619-628. 10.1016/S0092-8674(00)81382-3.CrossRefPubMed
5.
Remacle-Bonnet MM, Garrouste FL, Heller S, Andre F, Marvaldi JL, Pommier GJ: Insulin-like growth factor-I protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. Cancer Res. 2000, 60 (7): 2007-2017.PubMed
6.
Samani AA, Yakar S, LeRoith D, Brodt P: The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007, 28 (1): 20-47.CrossRefPubMed
7.
Probst-Hensch NM, Yuan JM, Stanczyk FZ, Gao YT, Ross RK, Yu MC: IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai. Br J Cancer. 2001, 85 (11): 1695-1699. 10.1054/bjoc.2001.2172.CrossRefPubMedPubMedCentral
8.
Palmqvist R, Hallmans G, Rinaldi S, Biessy C, Stenling R, Riboli E, Kaaks R: Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden. Gut. 2002, 50 (5): 642-646. 10.1136/gut.50.5.642.CrossRefPubMedPubMedCentral
9.
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999, 91 (7): 620-625. 10.1093/jnci/91.7.620.CrossRefPubMed
10.
Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E: Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst. 2000, 92 (19): 1592-1600. 10.1093/jnci/92.19.1592.CrossRefPubMed
11.
Tricoli JV, Rall LB, Karakousis CP, Herrera L, Petrelli NJ, Bell GI, Shows TB: Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res. 1986, 46 (12 Pt 1): 6169-6173.PubMed
12.
Lambert S, Vivario J, Boniver J, Gol-Winkler R: Abnormal expression and structural modification of the insulin-like growth-factor-II gene in human colorectal tumors. Int J Cancer. 1990, 46 (3): 405-410. 10.1002/ijc.2910460313.CrossRefPubMed
13.
Li SR, Ng CF, Banerjea A, Ahmed S, Hands R, Powar M, Ogunkolade W, Dorudi S, Bustin SA: Differential expression patterns of the insulin-like growth factor 2 gene in human colorectal cancer. Tumour Biol. 2004, 25 (1–2): 62-68.CrossRefPubMed
14.
Freier S, Weiss O, Eran M, Flyvbjerg A, Dahan R, Nephesh I, Safra T, Shiloni E, Raz I: Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon. Gut. 1999, 44 (5): 704-708. 10.1136/gut.44.5.704.CrossRefPubMedPubMedCentral
15.
Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB: Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer. 2002, 95 (10): 2086-2095. 10.1002/cncr.10945.CrossRefPubMed
16.
17.
Hewish M, Chau I, Cunningham D: Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009, 4 (1): 54-72. 10.2174/157489209787002515.CrossRefPubMed
18.
King ER, Wong KK: Insulin-like growth factor: current concepts and new developments in cancer therapy. Recent Pat Anticancer Drug Discov. 2012, 7 (1): 14-30. 10.2174/157489212798357930.CrossRefPubMedPubMedCentral
19.
Olmos D, Basu B, de Bono JS: Targeting insulin-like growth factor signaling: rational combination strategies. Mol Cancer Ther. 2010, 9 (9): 2447-2449. 10.1158/1535-7163.MCT-10-0719.CrossRefPubMed
20.
Gualberto A, Pollak M: Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 2009, 28 (34): 3009-3021. 10.1038/onc.2009.172.CrossRefPubMed
21.
Reidy DL, Vakiani E, Fakih MG, Saif MW, Hecht JR, Goodman-Davis N, Hollywood E, Shia J, Schwartz J, Chandrawansa K, et al: Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer. J Clin Oncol. 2010, 28 (27): 4240-4246. 10.1200/JCO.2010.30.4154.CrossRefPubMedPubMedCentral
22.
Favelyukis S, Till JH, Hubbard SR, Miller WT: Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol. 2001, 8 (12): 1058-1063. 10.1038/nsb721.CrossRefPubMed
23.
Pautsch A, Zoephel A, Ahorn H, Spevak W, Hauptmann R, Nar H: Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation. Structure. 2001, 9 (10): 955-965. 10.1016/S0969-2126(01)00655-4.CrossRefPubMed
24.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, et al: Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004, 5 (3): 221-230. 10.1016/S1535-6108(04)00050-9.CrossRefPubMed
25.
Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M: Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004, 64 (1): 236-242. 10.1158/0008-5472.CAN-03-2522.CrossRefPubMed
26.
Vasilcanu D, Girnita A, Girnita L, Vasilcanu R, Axelson M, Larsson O: The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway. Oncogene. 2004, 23 (47): 7854-7862. 10.1038/sj.onc.1208065.CrossRefPubMed
27.
Stromberg T, Ekman S, Girnita L, Dimberg LY, Larsson O, Axelson M, Lennartsson J, Hellman U, Carlson K, Osterborg A, et al: IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells. Blood. 2006, 107 (2): 669-678. 10.1182/blood-2005-01-0306.CrossRefPubMed
28.
Menu E, Jernberg-Wiklund H, De Raeve H, De Leenheer E, Coulton L, Gallagher O, Van Valckenborgh E, Larsson O, Axelson M, Nilsson K, et al: Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival. Int J Cancer. 2007, 121 (8): 1857-1861. 10.1002/ijc.22845.CrossRefPubMed
29.
Menu E, Jernberg-Wiklund H, Stromberg T, De Raeve H, Girnita L, Larsson O, Axelson M, Asosingh K, Nilsson K, Van Camp B, et al: Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood. 2006, 107 (2): 655-660. 10.1182/blood-2005-01-0293.CrossRefPubMed
30.
Yin S, Girnita A, Stromberg T, Khan Z, Andersson S, Zheng H, Ericsson C, Axelson M, Nister M, Larsson O, et al: Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 2010, 12 (1): 19-27. 10.1093/neuonc/nop008.CrossRefPubMed
31.
Muzny DM, Bainbridge MN, Chang K, et al: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012, 487 (7407): 330-337. 10.1038/nature11252.CrossRef
32.
Bellail AC, Olson JJ, Yang X, Chen ZJ, Hao C: A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov. 2012, 2 (2): 140-155. 10.1158/2159-8290.CD-11-0172.CrossRefPubMedPubMedCentral
33.
Liu Y, Bodmer WF: Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. Proc Natl Acad Sci USA. 2006, 103 (4): 976-981. 10.1073/pnas.0510146103.CrossRefPubMedPubMedCentral
34.
Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Harris EI, Washington MK, Brunt EM, Zaika A, Kim RB, et al: Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Res. 2008, 68 (24): 10315-10323. 10.1158/0008-5472.CAN-08-1984.CrossRefPubMedPubMedCentral
35.
Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O: Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and beta-arrestin1. Oncogene. 2008, 27 (11): 1629-1638. 10.1038/sj.onc.1210797.CrossRefPubMed
36.
Girnita L, Girnita A, Larsson O: Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci USA. 2003, 100 (14): 8247-8252. 10.1073/pnas.1431613100.CrossRefPubMedPubMedCentral
37.
Vasilcanu R, Vasilcanu D, Sehat B, Yin S, Girnita A, Axelson M, Girnita L: Insulin-like growth factor type-I receptor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 but not Akt (protein kinase B) can be induced by picropodophyllin. Mol Pharmacol. 2008, 73 (3): 930-939.CrossRefPubMed
38.
Zheng H, Shen H, Oprea I, Worrall C, Stefanescu R, Girnita A, Girnita L: beta-arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing’s sarcoma. Proc Natl Acad Sci USA. 2012, 109 (50): 20620-20625. 10.1073/pnas.1216348110.CrossRefPubMedPubMedCentral
39.
Bellail AC, Tse MC, Song JH, Phuphanich S, Olson JJ, Sun SY, Hao C: DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med. 2010, 14 (6A): 1303-1317. 10.1111/j.1582-4934.2009.00777.x.CrossRefPubMed
40.
Du C, Fang M, Li Y, Li L, Wang X: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000, 102 (1): 33-42. 10.1016/S0092-8674(00)00008-8.CrossRefPubMed
41.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000, 102 (1): 43-53. 10.1016/S0092-8674(00)00009-X.CrossRefPubMed
42.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 2012, 62 (1): 10-29. 10.3322/caac.20138.CrossRefPubMed
43.
Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR, Vogelstein B, Kinzler KW: Gene expression profiles in normal and cancer cells. Science. 1997, 276 (5316): 1268-1272. 10.1126/science.276.5316.1268.CrossRefPubMed
44.
Hakam A, Yeatman TJ, Lu L, Mora L, Marcet G, Nicosia SV, Karl RC, Coppola D: Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol. 1999, 30 (10): 1128-1133. 10.1016/S0046-8177(99)90027-8.CrossRefPubMed
45.
Ji QS, Mulvihill MJ, Rosenfeld-Franklin M, Cooke A, Feng L, Mak G, O’Connor M, Yao Y, Pirritt C, Buck E, et al: A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. Mol Cancer Ther. 2007, 6 (8): 2158-2167. 10.1158/1535-7163.MCT-07-0070.CrossRefPubMed
46.
Flanigan SA, Pitts TM, Eckhardt SG, Tentler JJ, Tan AC, Thorburn A, Leong S: The insulin-like growth factor I receptor/insulin receptor tyrosine kinase inhibitor PQIP exhibits enhanced antitumor effects in combination with chemotherapy against colorectal cancer models. Clin Cancer Res. 2010, 16 (22): 5436-5446. 10.1158/1078-0432.CCR-10-2054.CrossRefPubMedPubMedCentral
47.
Kaulfuss S, Burfeind P, Gaedcke J, Scharf JG: Dual silencing of insulin-like growth factor-I receptor and epidermal growth factor receptor in colorectal cancer cells is associated with decreased proliferation and enhanced apoptosis. Mol Cancer Ther. 2009, 8 (4): 821-833. 10.1158/1535-7163.MCT-09-0058.CrossRefPubMed
48.
Hu YP, Patil SB, Panasiewicz M, Li W, Hauser J, Humphrey LE, Brattain MG: Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor. Cancer Res. 2008, 68 (19): 8004-8013. 10.1158/0008-5472.CAN-08-0280.CrossRefPubMedPubMedCentral
49.
Fridman JS, Lowe SW: Control of apoptosis by p53. Oncogene. 2003, 22 (56): 9030-9040. 10.1038/sj.onc.1207116.CrossRefPubMed
Metadata
Title
The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin
Authors
Quan Wang
Feng Wei
Guoyue Lv
Chunsheng Li
Tongjun Liu
Costas G Hadjipanayis
Guikai Zhang
Chunhai Hao
Anita C Bellail
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-521

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