c-Jun N-terminal kinase 2 suppresses pancreatic cancer growth and invasion and is opposed by c-Jun N-terminal kinase 1.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
09
07
2020
accepted:
11
12
2020
revised:
11
12
2020
pubmed:
3
2
2021
medline:
5
4
2022
entrez:
2
2
2021
Statut:
ppublish
Résumé
The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 can act as either tumor suppressors or pro-oncogenic kinases in human cancers. The isoform-specific roles for JNK1 and JNK2 in human pancreatic cancer are still unclear, the question which should be addressed in this project. Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 clones were established either expressing either JNK1 or -2 shRNA in a stable manner. Basal anchorage-dependent and -independent cell growth, single-cell movement, and invasion using the Boyden chamber assay were analyzed. Xenograft growth was assessed using an orthotopic mouse model. All seven tested pancreatic cancer cell lines expressed JNKs as did human pancreatic cancer samples determined by immunohistochemistry. Pharmacological, unspecific JNK inhibition (SP600125) reduced cell growth of all cell lines but PANC-1. Especially inhibition of JNK2 resulted in overall increased oncogenic potential with increased proliferation and invasion, associated with alterations in cytoskeleton structure. Specific inhibition of JNK1 revealed opposing functions. Overall, JNK1 and JNK2 can exert different functions in human pancreatic cancer and act as counter players for tumor invasion. Specifically modulating the activity of JNKs may be of potential therapeutic interest in the future.
Identifiants
pubmed: 33526844
doi: 10.1038/s41417-020-00290-5
pii: 10.1038/s41417-020-00290-5
pmc: PMC8761571
doi:
Substances chimiques
Mitogen-Activated Protein Kinase 9
EC 2.7.1.24
Mitogen-Activated Protein Kinase 8
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
73-86Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : TR 1663/1
Informations de copyright
© 2021. The Author(s).
Références
Siegel RL, Miller KD, Jemal A. Cancer statistics 2019. CA Cancer J Clin. 2019;69:7–34.
doi: 10.3322/caac.21551
Hidalgo M, Cascinu S, Kleeff J, Labianca R, Lohr JM, Neoptolemos J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology. 2015;15:8–18.
doi: 10.1016/j.pan.2014.10.001
Dunne RF, Hezel AF. Genetics and biology of pancreatic ductal adenocarcinoma. Hematol Oncol Clin North Am. 2015;29:595–608.
doi: 10.1016/j.hoc.2015.04.003
Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Prim. 2016;2:16022.
doi: 10.1038/nrdp.2016.22
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–52.
doi: 10.1016/S0092-8674(00)00116-1
Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996;15:2760–70.
doi: 10.1002/j.1460-2075.1996.tb00636.x
Zeke A, Misheva M, Remenyi A, Bogoyevitch MA. JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev. 2016;80:793–835.
doi: 10.1128/MMBR.00043-14
Bode AM, Dong Z. The functional contrariety of JNK. Mol Carcinog. 2007;46:591–8.
doi: 10.1002/mc.20348
Dhanasekaran DN, Reddy EP. JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer. 2017;8:682–94.
doi: 10.18632/genesandcancer.155
Tournier C. The 2 faces of JNK signaling in cancer. Genes Cancer. 2013;4:397–400.
doi: 10.1177/1947601913486349
Bode AM, Dong Z. The functional contrariety of JNK. Mol Carcinogenesis. 2007;46:591–8.
doi: 10.1002/mc.20348
Gkouveris I, Nikitakis NG. Role of JNK signaling in oral cancer: a mini review. Tumour Biol. 2017;39:1010428317711659.
doi: 10.1177/1010428317711659
Wagner EF, Nebreda ÁR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537.
doi: 10.1038/nrc2694
Takahashi R, Hirata Y, Sakitani K, Nakata W, Kinoshita H, Hayakawa Y, et al. Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer. Cancer Sci. 2013;104:337–44.
doi: 10.1111/cas.12080
Okada M, Shibuya K, Sato A, Seino S, Suzuki S, Seino M, et al. Targeting the K-Ras-JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. Oncotarget. 2014;5:5100–12.
doi: 10.18632/oncotarget.2087
Liu Z, Neiss N, Zhou S, Henne-Bruns D, Korc M, Bachem M, et al. Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth. Cancer Res. 2007;67:2712–9.
doi: 10.1158/0008-5472.CAN-06-3843
Kornmann M, Ishiwata T, Matsuda K, Lopez ME, Fukahi K, Asano G, et al. IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells. Gastroenterology. 2002;123:301–13.
doi: 10.1053/gast.2002.34174
Traub B, Sun L, Ma Y, Xu P, Lemke J, Paschke S, et al. Endogenously expressed IL-4Ralpha promotes the malignant phenotype of human pancreatic cancer in vitro and in vivo. Int J Mol Sci.; 2017. https://doi.org/10.3390/ijms18040716.
Tepel J, Kruse M, March C, Fiedler A, Kapischke M, Ketterer T, et al. Terminally modified oligodeoxynucleotides directed against p53 in an orthotopic xenograft model: a novel adjuvant treatment strategy for pancreatic ductal carcinoma. Pancreas. 2004;28:1–12.
doi: 10.1097/00006676-200401000-00001
Sato T, Shibata W, Hikiba Y, Kaneta Y, Suzuki N, Ihara S, et al. c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice. Cancer Sci. 2017;108:2156–65.
doi: 10.1111/cas.13382
Yuan XP, Dong M, Li X, Zhou JP. GRP78 promotes the invasion of pancreatic cancer cells by FAK and JNK. Mol Cell Biochem. 2015;398:55–62.
doi: 10.1007/s11010-014-2204-2
Suzuki S, Okada M, Shibuya K, Seino M, Sato A, Takeda H, et al. JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells. Oncotarget. 2015;6:458–70.
doi: 10.18632/oncotarget.2693
Recio-Boiles A, Ilmer M, Rhea PR, Kettlun C, Heinemann ML, Ruetering J, et al. JNK pathway inhibition selectively primes pancreatic cancer stem cells to TRAIL-induced apoptosis without affecting the physiology of normal tissue resident stem cells. Oncotarget. 2016;7:9890–906.
doi: 10.18632/oncotarget.7066
Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell. 2004;15:713–25.
doi: 10.1016/j.molcel.2004.08.028
Huang C, Rajfur Z, Borchers C, Schaller MD, Jacobson K. JNK phosphorylates paxillin and regulates cell migration. Nature. 2003;424:219.
doi: 10.1038/nature01745
Collins CS, Hong J, Sapinoso L, Zhou Y, Liu Z, Micklash K, et al. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci USA. 2006;103:3775–80.
doi: 10.1073/pnas.0600040103
Ponz-Sarvise M, Tuveson DA, Kenneth HY. Mouse models of pancreatic ductal adenocarcinoma. Hematol Oncol Clin. 2015;29:609–17.
doi: 10.1016/j.hoc.2015.04.010
Qiu W, Su GH. Development of orthotopic pancreatic tumor mouse models. Pancreatic Cancer. Springer; 2013. p. 215–23.
Gradiz R, Silva HC, Carvalho L, Botelho MF, Mota-Pinto A. MIA PaCa-2 and PANC-1–pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 2016;6:21648.
doi: 10.1038/srep21648
Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Investig. 2009;119:1417–9.
doi: 10.1172/JCI39675
Liu CY, Lin HH, Tang MJ, Wang YK. Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation. Oncotarget. 2015;6:15966–83.
doi: 10.18632/oncotarget.3862
Kidd ME, Shumaker DK, Ridge KM. The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol. 2014;50:1–6.
pubmed: 23980547
pmcid: 3930939
doi: 10.1165/rcmb.2013-0314TR
Gilles C, Newgreen DF, Sato H, Thompson EW. Matrix metalloproteases and epithelial-to-mesenchymal transition. Rise and fall of epithelial phenotype. Springer; 2005. p. 297–315.
Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 1998;58:1048–51.
pubmed: 9500469