Traf2 ve Nck Etkileşimli Protein Kinaz (TNIK) Inhibitörünün Metastatik Köpek Meme Tümör Hücrelerinde Apoptotik Etkisinin Belirlenmesi
Abstract
ÖZ
Amaç: Köpek meme tümörleri (KMT) dişi köpeklerde en sık görülen tümörlerdir ve kullanılan başlıca tedavi seçeneği olarak cerrahi ciddi komplikasyonlara neden olmaktadır. Bu nedenle KMT için yeni tedavi seçeneklerine ihtiyaç duyulmaktadır. Traf2 ve Nck ile etkileşime giren serin protein kinaz (TNIK) WNT hedef genlerinin transkripsiyonel bir düzenleyicisidir ve meme kanseri gelişiminde yüksek oranda eksprese edilmektedir. TNIK'in inhibisyonu, anormal WNT sinyali olan kanserlerde yeni bir terapötik hedef olabilir. Bu nedenle, bu çalışmada NCB-0846'nın metastatik sarkom KMT alt tipi üzerindeki potansiyel terapötik etkisini ilk kez araştırılması amaçlanmıştır.
Materyal ve Metot: NCB-0846'nın KMT hücreleri üzerindeki sitotoksik ve apoptotik etkileri, WST‑1, Annexin V, hücre döngüsü, akridin oranj (AO) ve DAPI boyama ile analiz edilmiştir.
Bulgular: Elde edilen verilere göre NCB-0846, doza ve zamana bağlı anlamlı bir şekilde KMT hücre canlılığını azaltmış ve nükleer hasara sebep olmuştur. Ayrıca, NCB-0846, G0/G1 fazında hücrelerin birikmesi yoluyla apoptotik hücre ölümünü indüklemiştir.
Sonuç: Sonuç olarak elde ettiğimiz bulgular, NCB-0846'nın potansiyel olarak KMT için yeni bir terapötik anti-kanser ajan olabileceğini göstermektedir. Bununla birlikte KMT hücreleri üzerinde NCB-0846’nın TNIK ve Wnt sinyalinin inhibe edici aktivitesinin aydınlatılmasına yönelik daha ileri araştırmalara ihtiyaç duyulmaktadır.
Keywords
References
- Moulton JE. Tumors of the Mammary Gland, Moulton JE (ed), Tumors in Domestic Animals, 3 rd Ed. California; University of California Press; 1990.
- Doré M, Lanthier I, Sirois J. Cyclooxygenase-2 expression in canine mammary tumors. Vet Pathol. 2003;40(2):207-212. doi:10.1354/vp.40-2-207
- Hellmén E. Complex mammary tumours in the female dog: a review. J Dairy Res. 2005. doi:10.1017/s002202990500124x
- Saba CF, Rogers KS, Newman SJ, Mauldin GE, Vail DM. Mammary gland tumors in male dogs. J Vet Intern Med. 2007;21(5):1056-1059. doi:10.1892/0891-6640(2007)21[1056:mgtimd]2.0.co;2
- Sleeckx N, de Rooster H, Veldhuis Kroeze EJ, Van Ginneken C, Van Brantegem L. Canine mammary tumours, an overview. Reprod Domest Anim. 2011;46(6):1112-1131. doi:10.1111/j.1439-0531.2011.01816.x
- Serin G, Aydoğan A. Chondrosarcoma in the mammary gland of a bitch: A case report, Veterinarni Medicina. 2009;54(11):543-546.
- Soderstrom MJ, Gilson SD. Principles of surgical oncology. Vet Clin North Am Small Anim Pract. 1995;25(1):97-110. doi:10.1016/s0195-5616(95)50007-5
- Sugano T, Masuda M, Takeshita F, et al. Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846. Br J Cancer. 2021;124(1):228-236. doi:10.1038/s41416-020-01162-3
- Sun Y, Gao X, Wu P, et al. Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT). Phytomedicine. 2019;63:153015. doi:10.1016/j.phymed.2019.153015
- Jin J, Jung HY, Wang Y, et al. Nuclear expression of phosphorylated TRAF2- and NCK-interacting kinase in hepatocellular carcinoma is associated with poor prognosis. Pathol Res Pract. 2014;210(10):621-627. doi:10.1016/j.prp.2013.10.007
- Shitashige M, Satow R, Jigami T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70(12):5024-5033. doi:10.1158/0008-5472.CAN-10-0306
- Mahmoudi T, Li VS, Ng SS, et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009;28(21):3329-3340. doi:10.1038/emboj.2009.285
- Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther. 2015;156:1-9. doi:10.1016/j.pharmthera.2015.10.009
- Zhang Y, Jiang H, Qin M, Su X, Cao Z, Wang J. TNIK serves as a novel biomarker associated with poor prognosis in patients with pancreatic cancer. Tumour Biol. 2016;37(1):1035-1040. doi:10.1007/s13277-015-3881-5
- Takahashi H, Ishikawa T, Ishiguro M, et al. Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. BMC Cancer. 2015;15:794. doi:10.1186/s12885-015-1783-y
- Yamada T, Masuda M. Emergence of TNIK inhibitors in cancer therapeutics. Cancer Sci. 2017;108(5):818-823. doi:10.1111/cas.13203
- Sato K, Padgaonkar AA, Baker SJ, et al. Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nat Commun. 2021;12(1):4671. doi:10.1038/s41467-021-24878-z
- Goldschmidt MH, Shofer FS, Smelstoys JA. Neoplastic lesions of the mammary gland. In: Mohr U (ed) Pathobiology of the aging dog. Iowa State University Press; 2001:168–178.
- Turna O, Baykal A, Sozen Kucukkara E, et al. Efficacy of 5-aminolevulinic acid-based photodynamic therapy in different subtypes of canine mammary gland cancer cells. Lasers Med Sci. 2021. doi:10.1007/s10103-021-03324-y
- Masuda M, Uno Y, Ohbayashi N, et al. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun. 2016;7:12586. doi:10.1038/ncomms12586
- Kim J, Moon SH, Kim BT, Chae CH, Lee JY, Kim SH. A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells. PLoS One. 2014;9(10):e110180. doi:10.1371/journal.pone.0110180
Determination of the Apoptotic Effect of Raf2 and Nck-Interacting Protein Kinase Inhibitor on Metastatic Canine Mammary Gland Tumor Cells
Abstract
Objective: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs and the main treatment options used in CMGTs are surgery caused some complications. Therefore, new treatment options are needed for the CMGTs. Traf2 and Nck-interacting serine protein kinase (TNIK) as a transcriptional coregulator of Wnt targeted genes is highly expressed in breast cancer development. The inhibition of TNIK may be a new therapeutic target in cancers with abnormal WNT signaling. Therefore we aimed to investigate the potential therapeutic effect of NCB-0846 on metastatic sarcoma CMGTs subtype, for the first time.
Materials and Methods: The cytotoxic and apoptotic effects of NCB-0846 on CMGT cells were analyzed by WST‑1, Annexin V, cell cycle, acridine orange (AO) and DAPI staining.
Results: NCB-0846 significantly inhibited cell viability in a dose and time dependent manner (p<0.05) and induced nuclear damage in CMGT cells. Furthermore, NCB-0846 caused apoptotic cell death through the accumulation of cells in the G0/G1 phase.
Conclusion: Our findings demonstrated that NCB-0846 could be potentially a new therapeutic anti-cancer agent in the treatment of CMGTs. However, further investigations need to be performed in order to elucidate the inhibitory activity of TNIK and Wnt signaling by NCB-0846 on CMGT cells.
References
- Moulton JE. Tumors of the Mammary Gland, Moulton JE (ed), Tumors in Domestic Animals, 3 rd Ed. California; University of California Press; 1990.
- Doré M, Lanthier I, Sirois J. Cyclooxygenase-2 expression in canine mammary tumors. Vet Pathol. 2003;40(2):207-212. doi:10.1354/vp.40-2-207
- Hellmén E. Complex mammary tumours in the female dog: a review. J Dairy Res. 2005. doi:10.1017/s002202990500124x
- Saba CF, Rogers KS, Newman SJ, Mauldin GE, Vail DM. Mammary gland tumors in male dogs. J Vet Intern Med. 2007;21(5):1056-1059. doi:10.1892/0891-6640(2007)21[1056:mgtimd]2.0.co;2
- Sleeckx N, de Rooster H, Veldhuis Kroeze EJ, Van Ginneken C, Van Brantegem L. Canine mammary tumours, an overview. Reprod Domest Anim. 2011;46(6):1112-1131. doi:10.1111/j.1439-0531.2011.01816.x
- Serin G, Aydoğan A. Chondrosarcoma in the mammary gland of a bitch: A case report, Veterinarni Medicina. 2009;54(11):543-546.
- Soderstrom MJ, Gilson SD. Principles of surgical oncology. Vet Clin North Am Small Anim Pract. 1995;25(1):97-110. doi:10.1016/s0195-5616(95)50007-5
- Sugano T, Masuda M, Takeshita F, et al. Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846. Br J Cancer. 2021;124(1):228-236. doi:10.1038/s41416-020-01162-3
- Sun Y, Gao X, Wu P, et al. Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT). Phytomedicine. 2019;63:153015. doi:10.1016/j.phymed.2019.153015
- Jin J, Jung HY, Wang Y, et al. Nuclear expression of phosphorylated TRAF2- and NCK-interacting kinase in hepatocellular carcinoma is associated with poor prognosis. Pathol Res Pract. 2014;210(10):621-627. doi:10.1016/j.prp.2013.10.007
- Shitashige M, Satow R, Jigami T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70(12):5024-5033. doi:10.1158/0008-5472.CAN-10-0306
- Mahmoudi T, Li VS, Ng SS, et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009;28(21):3329-3340. doi:10.1038/emboj.2009.285
- Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther. 2015;156:1-9. doi:10.1016/j.pharmthera.2015.10.009
- Zhang Y, Jiang H, Qin M, Su X, Cao Z, Wang J. TNIK serves as a novel biomarker associated with poor prognosis in patients with pancreatic cancer. Tumour Biol. 2016;37(1):1035-1040. doi:10.1007/s13277-015-3881-5
- Takahashi H, Ishikawa T, Ishiguro M, et al. Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. BMC Cancer. 2015;15:794. doi:10.1186/s12885-015-1783-y
- Yamada T, Masuda M. Emergence of TNIK inhibitors in cancer therapeutics. Cancer Sci. 2017;108(5):818-823. doi:10.1111/cas.13203
- Sato K, Padgaonkar AA, Baker SJ, et al. Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nat Commun. 2021;12(1):4671. doi:10.1038/s41467-021-24878-z
- Goldschmidt MH, Shofer FS, Smelstoys JA. Neoplastic lesions of the mammary gland. In: Mohr U (ed) Pathobiology of the aging dog. Iowa State University Press; 2001:168–178.
- Turna O, Baykal A, Sozen Kucukkara E, et al. Efficacy of 5-aminolevulinic acid-based photodynamic therapy in different subtypes of canine mammary gland cancer cells. Lasers Med Sci. 2021. doi:10.1007/s10103-021-03324-y
- Masuda M, Uno Y, Ohbayashi N, et al. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun. 2016;7:12586. doi:10.1038/ncomms12586
- Kim J, Moon SH, Kim BT, Chae CH, Lee JY, Kim SH. A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells. PLoS One. 2014;9(10):e110180. doi:10.1371/journal.pone.0110180
Details
| Primary Language | English |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Research article |
| Authors | |
| Publication Date | March 1, 2022 |
| Submission Date | December 15, 2021 |
| Acceptance Date | January 10, 2022 |
| Published in Issue | Year 2022 Volume: 7 Issue: 1 |
