TBOPP enhances the anticancer effect of cisplatin by inhibiting DOCK1 in renal cell carcinoma

Zhang,Wei; Zheng,Xiaoxiao; Xie,Shangzhi; Zhang,Shufen; Mao,Jiayan; Cai,Ying; Lu,Xuemei; Chen,Wei; Ni,Haibin; Xie,Liping

doi:10.3892/mmr.2020.11243

TBOPP enhances the anticancer effect of cisplatin by inhibiting DOCK1 in renal cell carcinoma

Authors:
- Wei Zhang
- Xiaoxiao Zheng
- Shangzhi Xie
- Shufen Zhang
- Jiayan Mao
- Ying Cai
- Xuemei Lu
- Wei Chen
- Haibin Ni
- Liping Xie
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Affiliations: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China, Department of General Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
Published online on: June 16, 2020 https://doi.org/10.3892/mmr.2020.11243
Pages: 1187-1194
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The treatment of renal cell carcinoma (RCC) with chemotherapy remains a challenge; therefore, improving the knowledge of the molecular mechanisms underlying RCC chemoresistance and developing novel therapeutic strategies is important. Dedicator of cytokinesis 1 (DOCK1), the first member of the DOCK family to be discovered, displays various roles during tumorigenesis; however, its role during RCC progression is not completely understood. Therefore, the present study aimed to clarify the function of DOCK1 and 1‑[2‑(3'‑(trifluoromethyl)‑(1,1'‑biphenyl)‑4‑yl)‑2‑oxoethyl]‑5‑pyrrolidinylsulfonyl‑2 (1H)‑pyridone (TBOPP), a DOCK1‑sensitive inhibitor, during RCC development and chemoresistance. The results of CCK‑8 and EdU assay indicated that TBOPP decreased RCC cell viability and proliferation compared with the control group, and sensitized RCC cells to cisplatin. Moreover, RCC cells with high DOCK1 expression levels displayed increased resistance to cisplatin, whereas DOCK1 knockdown enhanced the lethal effects of cisplatin on RCC cells. Furthermore, the results determined by western blotting, CCK‑8 and cell apoptosis assay indicated that TBOPP effectively reduced DOCK1 expression levels compared with the control group, and the TBOPP‑mediated cisplatin sensitizing effect was mediated by DOCK1 inhibition. The present study suggests that DOCK1 plays a vital role in RCC cell chemoresistance to cisplatin; therefore, TBOPP may serve as a novel therapeutic agent for RCC chemoresistance.

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1	Jonasch E, Gao J and Rathmell WK: Renal cell carcinoma. BMJ. 349:g47972014. View Article : Google Scholar : PubMed/NCBI
2	Rossi SH, Klatte T, Usher-Smith J and Stewart GD: Epidemiology and screening for renal cancer. World J Urol. 36:1341–1353. 2018. View Article : Google Scholar : PubMed/NCBI
3	Van Poppel H, Becker F, Cadeddu JA, Gill IS, Janetschek G, Jewett MA, Laguna MP, Marberger M, Montorsi F, Polascik TJ, et al: Treatment of localised renal cell carcinoma. Eur Urol. 60:662–672. 2011. View Article : Google Scholar : PubMed/NCBI
4	Vitale MG, Bracarda S, Cosmai L, Crocetti E, Di Lorenzo G, Lapini A, Mandressi A, Martorana G, Masini C, Montironi R, et al: Management of kidney cancer patients: 2018 guidelines of the Italian Medical Oncology Association (AIOM). Tumori. 105 (4_suppl):S3–S12. 2019. View Article : Google Scholar
5	Sánchez-Gastaldo A, Kempf E, González Del Alba A and Duran I: Systemic treatment of renal cell cancer: A comprehensive review. Cancer Treat Rev. 60:77–89. 2017. View Article : Google Scholar : PubMed/NCBI
6	Tanji N and Yokoyama M: Treatment of metastatic renal cell carcinoma and renal pelvic cancer. Clin Exp Nephrol. 15:331–338. 2011. View Article : Google Scholar : PubMed/NCBI
7	Yagoda A, Petrylak D and Thompson S: Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am. 20:303–321. 1993.PubMed/NCBI
8	Laurin M and Côté JF: Insights into the biological functions of Dock family guanine nucleotide exchange factors. Genes Dev. 28:533–547. 2014. View Article : Google Scholar : PubMed/NCBI
9	Morishita K, Anh Suong DN, Yoshida H and Yamaguchi M: The drosophila DOCK family protein Sponge is required for development of the air sac primordium. Exp Cell Res. 354:95–102. 2017. View Article : Google Scholar : PubMed/NCBI
10	Sanematsu F, Nishikimi A, Watanabe M, Hongu T, Tanaka Y, Kanaho Y, Côté JF and Fukui Y: Phosphatidic acid-dependent recruitment and function of the Rac activator DOCK1 during dorsal ruffle formation. J Biol Chem. 288:8092–8100. 2013. View Article : Google Scholar : PubMed/NCBI
11	Laurin M, Huber J, Pelletier A, Houalla T, Park M, Fukui Y, Haibe-Kains B, Muller WJ and Côté JF: Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis. Proc Natl Acad Sci USA. 110:7434–7439. 2013. View Article : Google Scholar : PubMed/NCBI
12	Chen DJ, Chen W, Jiang H, Yang H, Wang YC and Chen JH: Downregulation of DOCK1 sensitizes bladder cancer cells to cisplatin through preventing epithelial-mesenchymal transition. Drug Des Devel Ther. 10:2845–2853. 2016. View Article : Google Scholar : PubMed/NCBI
13	Zhang B, Li H, Yin C, Sun X, Zheng S, Zhang C, Shi L, Liu Y and Lu S: Dock1 promotes the mesenchymal transition of glioma and is modulated by MiR-31. Neuropathol Appl Neurobiol. 43:419–432. 2017. View Article : Google Scholar : PubMed/NCBI
14	Zhang G, Zhang J, Yang X, Zhang X, Yang S, Wang J, Hu K, Shi J, Ke X and Fu L: High expression of dedicator of cytokinesis 1 adversely influences the prognosis of acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. Cancer Manag Res. 11:3053–3060. 2019. View Article : Google Scholar : PubMed/NCBI
15	Gadea G and Blangy A: Dock-family exchange factors in cell migration and disease. Eur J Cell Biol. 93:466–477. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jarzynka MJ, Hu B, Hui KM, Bar-Joseph I, Gu W, Hirose T, Haney LB, Ravichandran KS, Nishikawa R and Cheng SY: ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res. 67:7203–7211. 2007. View Article : Google Scholar : PubMed/NCBI
17	Liang Y, Wang S and Zhang Y: Downregulation of Dock1 and Elmo1 suppresses the migration and invasion of triple-negative breast cancer epithelial cells through the RhoA/Rac1 pathway. Oncol Lett. 16:3481–3488. 2018.PubMed/NCBI
18	Pan Y and Li X, Duan J, Yuan L, Fan S, Fan J, Xiaokaiti Y, Yang H, Wang Y and Li X: Enoxaparin sensitizes human non-small-cell lung carcinomas to gefitinib by inhibiting DOCK1 expression, vimentin phosphorylation, and Akt activation. Mol Pharmacol. 87:378–390. 2015. View Article : Google Scholar : PubMed/NCBI
19	Tajiri H, Uruno T, Shirai T, Takaya D, Matsunaga S, Setoyama D, Watanabe M, Kukimoto-Niino M, Oisaki K, Ushijima M, et al: Targeting Ras-driven cancer cell survival and invasion through selective inhibition of DOCK1. Cell Rep. 19:969–980. 2017. View Article : Google Scholar : PubMed/NCBI
20	Tomino T, Tajiri H, Tatsuguchi T, Shirai T, Oisaki K, Matsunaga S, Sanematsu F, Sakata D, Yoshizumi T, Maehara Y, et al: DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1^P29S mutation. Biochem Biophys Res Commun. 497:298–304. 2018. View Article : Google Scholar : PubMed/NCBI
21	Zhang Y, Fang L, Zang Y, Ren J and Xu Z: CIP2A promotes proliferation, invasion and chemoresistance to cisplatin in renal cell carcinoma. J Cancer. 9:4029–4038. 2018. View Article : Google Scholar : PubMed/NCBI
22	Molina AM, Motzer RJ and Heng DY: Systemic treatment options for untreated patients with metastatic clear cell renal cancer. Semin Oncol. 40:436–443. 2013. View Article : Google Scholar : PubMed/NCBI
23	Namekata K, Kimura A, Kawamura K, Harada C and Harada T: Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration. Prog Retin Eye Res. 43:1–16. 2014. View Article : Google Scholar : PubMed/NCBI
24	Schmidt S and Debant A: Function and regulation of the Rho guanine nucleotide exchange factor Trio. Small GTPases. 5:e297692014. View Article : Google Scholar : PubMed/NCBI
25	Laurin M, Dumouchel A, Fukui Y and Côté JF: The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo. Small GTPases. 4:221–230. 2013. View Article : Google Scholar : PubMed/NCBI
26	Laurin M, Fradet N, Blangy A, Hall A, Vuori K and Côté JF: The atypical Rac activator Dock180 (Dock1) regulates myoblast fusion in vivo. Proc Natl Acad Sci USA. 105:15446–15451. 2008. View Article : Google Scholar : PubMed/NCBI
27	Albert ML, Kim JI and Birge RB: Alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol. 2:899–905. 2000. View Article : Google Scholar : PubMed/NCBI
28	Wang J, Dai JM, Che YL, Gao YM, Peng HJ, Liu B, Wang H and Linghu H: Elmo1 helps dock180 to regulate Rac1 activity and cell migration of ovarian cancer. Int J Gynecol Cancer. 24:844–850. 2014. View Article : Google Scholar : PubMed/NCBI
29	Li W, Xiong X, Abdalla A, Alejo S, Zhu L, Lu F and Sun H: HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion. J Biol Chem. 293:15397–15418. 2018. View Article : Google Scholar : PubMed/NCBI
30	Feng H, Hu B, Jarzynka MJ, Li Y, Keezer S, Johns TG, Tang CK, Hamilton RL, Vuori K, Nishikawa R, et al: Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. Proc Natl Acad Sci USA. 109:3018–3023. 2012. View Article : Google Scholar : PubMed/NCBI