c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.

College of Life Science Yangtze University Jingzhou China

College of Veterinary Medicine Nanjing Agricultural University Nanjing China

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro Brazil

Medical Faculty of the Military Medical Academy University of Defence Belgrade Serbia

National Poison Control Centre Military Medical Academy Belgrade Serbia

National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues Huazhong Agricultural University Wuhan China

Zobrazit více v PubMed

Gkouveris I, Nikitakis NG.. Role of JNK signaling in oral cancer: a mini review. Tumour Biol 2017;39:101042831771165. PubMed

Kumar A, Singh UK, Kini SG, et al. . JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases. Future Med Chem 2015;7:2065–86. PubMed

Zeke A, Misheva M, Reményi A, Bogoyevitch MA.. JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev 2016;80:793–835. PubMed PMC

Minero VG, Khadjavi A, Costelli P, et al. . JNK activation is required for TNFα-induced apoptosis in human hepatocarcinoma cells. Int Immunopharmacol 2013;17:92–8. PubMed

Bode AM, Dong Z.. The functional contrariety of JNK. Mol Carcinog 2007;46:591–8. PubMed PMC

Ventura J-J, Hübner A, Zhang C, et al. . Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell 2006;21:701–10. PubMed

Dhanasekaran DN, Reddy EP.. JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer 2017;8:682–94. PubMed PMC

15Suzuki S, Okada M, Shibuya K, et al. . JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells. Oncotarget 2014;6:458–70. PubMed PMC

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. PubMed

Peng B, Chai Y, Li Y, et al. . CIP2A overexpression induces autoimmune response and enhances JNK signaling pathway in human lung cancer. BMC Cancer 2015;15:895. PubMed PMC

Okada M, Shibuya K, Sato A, et al. . Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells. Oncol Rep 2013;30:1957–64. PubMed

Phelps-Polirer K, Abt MA, Smith D, Yeh ES.. Co-targeting of jnk and hunk in resistant her2-positive breast cancer. Plos One 2016;11:e0153025. PubMed PMC

Puvirajesinghe TM, Bertucci F, Jain A, et al. . Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. Nat Commun 2016;7:10318. PubMed PMC

Zhang JY, Selim MA.. The role of the c-Jun N-terminal Kinase signaling pathway in skin cancer. Am J Cancer Res 2012; 2:691–8. PubMed PMC

Gururajan M, Chui R, Karuppannan AK, et al. . c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells. Blood 2005;106:1382–91. PubMed PMC

Li W, Zhang H, Nie A, et al. . mTORC1 pathway mediates beta cell compensatory proliferation in 60% partial-pancreatectomy mice. Endocrine 2016;53:117–28. PubMed

He Y, Duckett D, Chen W, et al. . Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett 2014;24:161–4. PubMed PMC

Zhao HF, Wang J, Jiang HR, et al. . PI3K p110β isoform synergizes with JNK in the regulation of glioblastoma cell proliferation and migration through Akt and FAK inhibition. J Exp Clin Cancer Res 2016;35:78. PubMed PMC

Zhou Y, Wang Y, Zhao Z, et al. . 37LRP induces invasion in hypoxic lung adenocarcinoma cancer cells A549 through the JNK/ERK/c-Jun signaling cascade. Tumour Biol 2017;39:101042831770165. PubMed

Han J, Jeon M, Shin I, Kim S.. Elevated STC-1 augments the invasiveness of triple-negative breast cancer cells through activation of the JNK/c-Jun signaling pathway. Oncology Rep 2016;36:1764–71. PubMed

Liu G, Jiang X, Zhu X, et al. . Ros activates jnk-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. Acta Pharmacologica Sinica 2015; 36:1473–9. PubMed PMC

Lin A, Dibling B.. The true face of JNK activation in apoptosis. Aging Cell 2002; 1:112–6. PubMed

Ruan J, Qi Z, Shen L, et al. . Crosstalk between JNK and NF-κB signaling pathways via HSP27 phosphorylation in HepG2 cells. Biochem Biophys Res Commun 2015;456:122–8. PubMed

Svensson C, Part K, Künnis-Beres K, et al. . Pro-survival effects of JNK and p38 MAPK pathways in LPS-induced activation of BV-2 cells. Biochem Biophys Res Commun 2011;406:488–92. PubMed

Okamura T, Antoun G, Keir ST, et al. . Phosphorylation of glutathione S-transferase P1 (GSTP1) by epidermal growth factor receptor (EGFR) pomotes formation of the GSTP1-c-Jun N-terminal kinase (JNK) complex and suppresses JNK downstream signaling and apoptosis in brain tumor cells. J Biol Chem 2015;290:30866–78. PubMed PMC

Yin H, Yang X, Gu W, et al. . HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation. Oncotarget 2017;8:71642–56. PubMed PMC

Li J, Zhao L, Zhao X, et al. . Foxo1 attenuates NaF-induced apoptosis of LS8 cells through the JNK and mitochondrial pathways. Biol Trace Elem Res 2018;181:104–11. PubMed

Liu GY, Jiang XX, Zhu X, et al. . ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. Acta Pharmacol Sin 2015;36:1473–9. PubMed PMC

Almasi S, Kennedy BE, El-Aghil M, et al. . TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway. J Biol Chem 2018;293:3637–50. PubMed PMC

Huang XL, Zhang H, Yang XY, et al. . Activation of a c-Jun N-terminal kinase-mediated autophagy pathway attenuates the anticancer activity of gemcitabine in human bladder cancer cells. Anticancer Drug 2017;28:596–602. PubMed

Ren K, Mo ZC, Liu X, et al. . TGF-β down-regulates apolipoprotein M expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells. Lipids 2017;52:109–17. PubMed

Liang Y, Jiao J, Liang L, et al. . TRAF6 mediated the promotion of salivary adenoid cystic carcinoma progression through Smad-p38-JNK signaling pathway induced by TGF-β. J Oral Pathol Med 2018;47:583–9. PubMed

Mao CP, Wu T, Song KH, Kim TW.. Immune-mediated tumor evolution: Nanog links the emergence of a stem like cancer cell state and immune evasion. Oncoimmunology 2014;3:e947871. PubMed PMC

Abdollahi A, Folkman J.. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat 2010;13:16–28. PubMed

Ryoo HD, Gorenc T, Steller H.. Apoptotic cells can induce compensatory cell proliferation through the JNK and the wingless signaling pathways. Dev Cell 2004;7:491–501. PubMed

Vucur M, Reisinger F, Gautheron J, et al. . RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. Cell Rep 2013;4:776–90. PubMed

Poulton JS, Cuningham JC, Peifer M.. Acentrosomal drosophila epithelial cells exhibit abnormal cell division, leading to cell death and compensatory proliferation. Dev Cell 2014;30:731–45. PubMed PMC

Messoussi A, Feneyrolles C, Bros A, et al. . Recent progress in the design, study, and development of c-Jun N-terminal kinase inhibitors as anticancer agents. Chem Biol 2014; 21:1433–43. PubMed

Wu Q, Wu W, Fu B, et al. . JNK signaling in cancer cell survival. Med Res Rev 2019;39:2082–104. PubMed

Haynes NE, Scott NR, Chen LC, et al. . Identification of an adamantyl azaquinolone JNK selective inhibitor. ACS Med Chem Lett 2012;3:764–8. PubMed PMC

Ngoei KR, Catimel B, Church N, et al. . Characterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide. Biochem J 2011;434:399–413. PubMed

Chen Y, Song S, Su W.. Activation of JNK by TPA promotes apoptosis via PKC path way in gastric cancer cells. World J Gastroenterol 2002;8:1014–8. PubMed PMC

Androutsopoulos VP, Spandidos DA.. Anticancer pyridines induce G2/M arrest and apoptosis via p53 and JNK upregulation in liver and breast cancer cells. Oncol Rep 2018;39:519–24. PubMed PMC

Deng Y, Ren X, Yang L, et al. . A jnk-dependent pathway is required for tnfalpha-induced apoptosis. Cell 2003;115:61–70. PubMed

Cerezo D, Ruiz-Alcaraz AJ, Lencina-Guardiola M, et al. . Attenuated JNK signaling in multidrug-resistant leukemic cells. Dual role of MAPK in cell survival. Cell Signal 2017;30:162–70. PubMed

Yue WY, Clark JJ, Fernando A, et al. . Contribution of persistent C-Jun N-terminal kinase activity to the survival of human vestibular schwannoma cells by suppression of accumulation of mitochondrial superoxides. Neuro Oncol 2011;13:961–73. PubMed PMC

Granato M, Santarelli R, Lotti LV, et al. . JNK and macroautophagy activ ation by bortezomib has a pro-survival effect in primary effusion lymphoma cells. PLoS One 2013;8:e75965. PubMed PMC

Bubici C, Papa S.. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 2014;171:24–37. PubMed PMC

Greenman C, Stephens P, Smith R, et al. . Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153–8. PubMed PMC

Wagner EF, Nebreda AR.. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 2009;9:537–49. PubMed

Lee YS, Kim SY, Song SJ, Hong HK, et al. . Crosstalk between CCL7 and CCR3 promotes metastasis of colon cancer cells via ERK-JNK signaling pathways. Oncotarget 2016;7:36842–53. PubMed PMC

Ma J, Zhang L, Han W, et al. . Activation of JNK/c-Jun is required for the proliferation, survival and angiogenesis induced by EETs in PAECs. J Lipid Res 2012;53:1093–105. PubMed PMC

Tong X, Barbour M, Hou K, et al. . Interleukin-33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways. Mol Oncol 2016;10:113–25. PubMed PMC

Fang M, Li Y, Huang K, et al. . IL33 promotes colon cancer cell stemness via JNK activation and macrophage recruitment. Cancer Res 2017;77:2735–45. PubMed PMC

Sung Y, Park S, Park SJ, et al. . Jazf1 promotes prostate cancer progression by activating JNK/Slug. Oncotarget 2017; 9:755–65. PubMed PMC

Kitanaka C, Sato A, Okada M.. JNK signaling in the control of the tumor-initiating capacity associated with cancer Stem Cells. Genes Cancer 2013;4:388–96. PubMed PMC

Schmid CA, Robinson MD, Scheifinger NA, et al. . DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma. J Exp Med 2015; 212:775–92. PubMed PMC

Deng X, Xiao L, Lang W, et al. . Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 2001;276:23681–8. PubMed

Lamb JA, Ventura JJ, Hess P, et al. . JunD mediates survival signaling by the JNK signal transduction pathway. Mol Cell 2003;11:1479–89. PubMed

Himes SR, ester DP, Ravasi T, et al. . The JNK are important for development and survival of macrophages. J Immunol 2006;176:2219–28. PubMed

Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays 2003;25:17–24. PubMed

Lin A. A five-year itch in TNF-alpha cytotoxicity: the time factor determines JNK action. Dev Cell 2006; 10:277–8. PubMed

Tang F, Tang G, Xiang J, et al. . Absence of NF-kB-mediated inhibition of JNK activation contributes to TNF-a induced apoptosis in MCF-7 cells. Mol Cell Biol 2002;22:8571–9. PubMed PMC

Wu Q, Wang X, Wan D, et al. . Crosstalk of JNK1-STAT3 is critical for RAW264.7 cell survival. Cell Signal 2014;26:2951–60. PubMed

Cicenas J, Zalyte E, Rimkus A, et al. . JNK, p38, ERK, and SGK1 Inhibitors in Cancer. Cancers 2017;10:1. PubMed PMC

Montagut C, Settleman J.. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 2009;283:125–34. PubMed

Meng L, Huang Z.. In silico-in vitro discovery of untargeted kinase-inhibitor interactions from kinase-targeted therapies: a case study on the cancer MAPK signaling pathway. Comput Biol Chem 2018;75:196–204. PubMed

Bennett BL, Sasaki DT, Murray BW, et al. . SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 2001;98:13681–6. PubMed PMC

Zhang XJ, He C, Li P, et al. . Ginsenoside Rg1, a potential JNK inhibitor, protects against ischemia/reperfusion-induced liver damage. J Funct Foods 2015;15:580–92.

Grassi ES, Vezzoli V, Negri I, et al. . SP600125 has a remarkable anti-cancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways. Oncotarget 2015;6:36383–99. PubMed PMC

Cerbone A, Toaldo C, Pizzimenti S, et al. . AS601245, an anti-inflammatory JNK inhibitor, and clofibrate have a synergistic effect in inducing cell responses and in affecting the gene expression profile in CaCo-2 colon cancer cells. PPAR Res 2012;2012:1–16. PubMed PMC

Cerbone A, Toaldo C, Minelli R, et al. . Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in human colon cancer cells. PLoS One 2012;7:e40149. PubMed PMC

Ebelt ND, Kaoud TS, Edupuganti R, et al. . A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib. Oncotarget 2017;8:104894–912. PubMed PMC

Zhang T, Inesta-Vaquera F, Niepel M, et al. . Discovery of potent and selective covalent inhibitors of JNK. Chem Biol 2012;19:140–54. PubMed PMC

Flemming A. Fungal infection: JNK inhibitors boost antifungal immunity. Nat Rev Immunol 2017;17:149. PubMed

Okada M, Kuramoto K, Takeda H, et al. . The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. Oncotarget 2016;7:27021–27032. PubMed PMC

Orci LA, Lacotte S, Oldani G, et al. . The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence. Dig Dis Sci 2014;59:2058–2068. PubMed

Jiang W, Wang Z, Jiang Y, et al. . Ginsenoside Rg1 ameliorates motor function in an animal model of Parkinson’s Disease. Pharmacology 2015;96:25–31. PubMed

Prasad KD, Trinath J, Biswas A, et al. . Alkyl chain substituted 1,9-pyrazoloanthrones exhibit prominent inhibitory effect on c-Jun N-terminal kinase (JNK). Org Biomol Chem 2014;12:4656–62. PubMed

Angell RM, Atkinson FL, Brown MJ, et al. . N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3. Bioorg Med Chem Lett 2007;17:1296–1301. PubMed

Jang WY, Lee JY, Lee ST, et al. . Inhibition of JNK2 and JNK3 by JNK inhibitor IX induces prometaphase arrest-dependent apoptotic cell death in human Jurkat T cells. Biochem Biophys Res Commun 2014;452:845–851. PubMed

Liu J, Liu A.. Role of JNK activation in apoptosis: a double-edged sword. Cell Res 2005;15:36–42. PubMed

Borsello T, Clarke PG, Hirt L, et al. . A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 2003;9:1180–6. PubMed

Stebbins JL, De SK, Machleidt T, et al. . Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proc Natl Acad Sci U S A 2008;105:16809–13. PubMed PMC

Asano Y, Kitamura S, Ohra T, et al. . Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1). Bioorg Med Chem 2008;16:4715–32. PubMed

Yao K, Cho YY, Bode AM, et al. . A selective small-molecule inhibitor of c-Jun N-terminal kinase 1. FEBS Lett 2009;583:2208–12. PubMed

Manning AM, Davis RJ.. Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2003; 2:554–65. PubMed

Neitz RJ, Konradi AW, Sham HL, et al. . Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement. Bioorg Med Chem Lett 2011;21:3726–9. PubMed

Swahn B-M, Huerta F, Kallin E, et al. . Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg Med Chem Lett 2005;15:5095–9. PubMed

Swahn BM, Xue Y, Arzel E, et al. . Design and synthesis of 20-anilino-4,40-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg Med Chem Lett 2006;16:1397–401. PubMed

Zhao Y, Spigolon G, Bonny C, et al. . The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. Mol Cell Neurosci 2012;49:300–10. PubMed

Zheng K, Park CM, Iqbal S, et al. . Pyridopyrimidinone derivatives as potent and selective c-Jun N-terminal kinase (JNK) inhibitors. ACS Med Chem Lett 2015;6:413–8. PubMed PMC

Kersting S, Behrendt V, Kersting J, et al. . The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium. J Inflamm Res 2013;6:71–81. PubMed PMC

Plantevin Krenitsky V, Nadolny L, Delgado M, et al. . Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett 2012; 22:1433–8. PubMed

Karin M, Gallagher E.. From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 2005;57:283–95. PubMed

Gao YJ, Cheng JK, Zeng Q, et al. . Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol 2009;219:146–55. PubMed PMC

Posthumadeboer J, van Egmond PW, Helder MN, et al. . Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin. Oncotarget 2012;3:1169–81. PubMed PMC

Zhang H, Niu X, Qian Z, et al. . The c-Jun N-terminal kinase inhibitor SP600125 inhibits human cytomegalovirus replication. J Med Virol 2015;87:2135–44. PubMed

Beydoun T, Deloche C, Perino J, et al. . Subconjunctival injection of XG-102, a JNK inhibitor peptide, in patients with intraocular inflammation: a safety and tolerability study. J Ocul Pharmacol Ther 2015;31:93–9. PubMed

Desir S, O’Hare P, Vogel RI, et al. . Chemotherapy-induced tunneling nanotubes mediate intercellular drug efflux in pancreatic cancer. Sci Rep 2018;8:9484. PubMed PMC

Gong L, Tan YC, Boice G, et al. . Discovery of a novel series of 4-quinolone JNK inhibitors. Bioorg Med Chem Lett 2012;22:7381–7 PubMed

He Y, Kamenecka TM, Shin Y, et al. . Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett 2011;21:1719–23. PubMed PMC

Ogura M, Uchida T, Terui Y, et al. . Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci 2015;106:896–901. PubMed PMC

Okusaka T, Ueno H, Ikeda M, et al. . Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res 2015;45:1283–91. PubMed

Mahadevan D, Chiorean EG, Harris WB, et al. . Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eu J Cancer 2012;48:3319–27. PubMed PMC

Makker V, Recio FO, Ma L, et al. . A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 2016;122:3519–28. PubMed PMC

Brown JR. How I treat CLL patients with ibrutinib. Blood 2018;131:379–86. PubMed