Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun
Received date: 06 Feb 2018
Accepted date: 14 Mar 2018
Published date: 21 Feb 2019
Copyright
Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for antimetastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
Wei Shao , Shasha Li , Lu Li , Kequan Lin , Xinhong Liu , Haiyan Wang , Huili Wang , Dong Wang . Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun[J]. Protein & Cell, 2019 , 10(3) : 161 -177 . DOI: 10.1007/s13238-018-0533-8
1 |
Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M (1987) Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49:729–739
|
2 |
Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, Lecocke M, Metivier J, Booser D, Ibrahim N
|
3 |
Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA (1993) Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4:197–250
|
4 |
Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA
|
5 |
Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O, Eneman J, Crocker A, White J, Tessitore J
|
6 |
Chambers J, Angulo A, Amaratunga D, Guo H, Jiang Y, Wan JS, Bittner A, Frueh K, Jackson MR, Peterson PA
|
7 |
Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, Liu K, Huang S (2009) Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res 69:9228–9235
|
8 |
Clarke C, Madden SF, Doolan P, Aherne ST, Joyce H, O’Driscoll L, Gallagher WM, Hennessy BT, Moriarty M, Crown J
|
9 |
Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K, Massague J (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446:765–770
|
10 |
Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, Anders C, Ewend M, Perou CM (2012) Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat 132:523–535
|
11 |
Horak CE, Pusztai L, Xing G, Trifan OC, Saura C, Tseng LM, Chan S, Welcher R, Liu D (2013) Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clin Cancer Res 19:1587–1595
|
12 |
Howe LR, Chang SH, Tolle KC, Dillon R, Young LJ, Cardiff RD, Newman RA, Yang P, Thaler HT, Muller WJ
|
13 |
Iorio F, Bosotti R, Scacheri E, Belcastro V, Mithbaokar P, Ferriero R, Murino L, Tagliaferri R, Brunetti-Pierri N, Isacchi A
|
14 |
Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549
|
15 |
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN
|
16 |
Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, Sierra A, Boudinet A, Guinebretiere JM, Ricevuto E
|
17 |
Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P
|
18 |
Lee YT (1983) Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 23:175–180
|
19 |
Lee J, Liu J, Feng X, Salazar Hernandez MA, Mucka P, Ibi D, Choi JW, Ozcan U (2016) Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med 22:1023–1032
|
20 |
Li H, Qiu J, Fu XD (2012a) RASL-seq for massively parallel and quantitative analysis of gene expression. Curr Protoc Mol Biol.https://doi.org/10.1002/0471142727.mb0413s98
|
21 |
Li H, Zhou H, Wang D, Qiu J, Zhou Y, Li X, Rosenfeld MG, Ding S, Fu XD (2012b) Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery. Proc Natl Acad Sci USA 109:4609–4614
|
22 |
Li Q, Wang Y, Xiao H, Li Y, Kan X, Wang X, Zhang G, Wang Z, Yang Q, Chen X
|
23 |
Lopez-Bergami P, Lau E, Ronai Z (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65–76
|
24 |
Lu X, Lu X, Kang Y (2010) Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement. Cell Res 20:1012–1022
|
25 |
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524
|
26 |
Morrison DK (2012) MAP kinase pathways. Cold Spring Harb Perspect Biol 4:a011254
|
27 |
Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284
|
28 |
O’Hare T,Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q
|
29 |
Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874
|
30 |
Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massague J (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77
|
31 |
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA
|
32 |
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S (1995) Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol 13:1144–1151
|
33 |
Raney BJ, Cline MS, Rosenbloom KR, Dreszer TR, Learned K, Barber GP, Meyer LR, Sloan CA, Malladi VS, Roskin KM
|
34 |
Saito S, Furuno A, Sakurai J, Sakamoto A, Park HR, Shin-Ya K, Tsuruo T, Tomida A (2009) Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res 69:4225–4234
|
35 |
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30
|
36 |
Stegmaier K, Ross KN, Colavito SA, O’Malley S, Stockwell BR, Golub TR (2004) Gene expression-based high-throughput screening (GE-HTS) and application to leukemia differentiation. Nat Genet 36:257–263
|
37 |
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES
|
38 |
Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X,Gould J, Davis JF, Tubelli AA, Asiedu JK
|
39 |
Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP (2015) Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep 5:10194
|
40 |
van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT
|
41 |
Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, Yue CF, Xu J, Zheng FM, Chen JN, Kang Z
|
42 |
Wang J, Rouse C, Jasper JS, Pendergast AM (2016) ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling. Sci Signal 9:ra12
|
43 |
Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602
|
44 |
Wu Y, Zhang Y,Zhang H, Yang X, Wang Y, Ren F, Liu H, Zhai Y, Jia B, Yu J
|
45 |
Xiu YL, Sun KX, Chen X, Chen S, Zhao Y, Guo QG, Zong ZH (2017) Upregulation of the lncRNA Meg3 induces autophagy to inhibit tumorigenesis and progression of epithelial ovarian carcinoma by regulating activity of ATG3. Oncotarget 8:31714–31725
|
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