TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2

Guo,Zheng; Zhang,Xiufang; Zhu,Huabin; Zhong,Nanying; Luo,Xiaoning; Zhang,Yu; Tu,Fuping; Zhong,Jinghua; Wang,Xiangcai; He,Jue; Huang,Li

doi:10.3892/or.2020.7890

TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2

Authors:
- Zheng Guo
- Xiufang Zhang
- Huabin Zhu
- Nanying Zhong
- Xiaoning Luo
- Yu Zhang
- Fuping Tu
- Jinghua Zhong
- Xiangcai Wang
- Jue He
- Li Huang
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Affiliations: Department of Oncology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, First School of Clinical Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, Department of Pathology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
Published online on: December 9, 2020 https://doi.org/10.3892/or.2020.7890
Pages: 523-534
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is a common cancer worldwide, and its treatment strategies are limited. The underlying mechanism of CRC progression remains to be determined. Telomere maintenance 2 (TELO2) is a mTOR‑interacting protein. Both the role and molecular mechanism of TELO2 in cancer progression remain unknown. In this study, the gene expression database of normal and tumor tissue, in addition to western blot analysis, and immunohistochemistry (IHC) were used to determine the expression and location of TELO2 in CRC and normal tissues. Clinical features of a tissue array were collected and analyzed. WST‑1, soft agar, flow cytometry, wound healing, and invasion assays were employed to verify the role of TELO2 in the growth, cell cycle, migration, and invasion of CRC cells. The correlation between TELO2 and RICTOR (rapamycin‑insensitive companion of mTOR) was analyzed by bioinformatics, IHC, and immunoprecipitation. Normal and serum‑deprived cells were collected to detect the protein level of TELO2 and its downstream effectors. The results revealed that TELO2 was significantly upregulated in CRC, and TELO2 inhibition significantly restrained the growth, cell cycle, and metastasis of CRC cells. TELO2 overexpression correlated with age, lymph node metastasis, and TNM stage of CRC patients. In addition, TELO2 was positively correlated with RICTOR in CRC and induced tumor progression mainly via RICTOR with serum in culture. RICTOR induced the degradation of TELO2 upon serum deprivation in an mTOR‑independent manner. These findings indicate that TELO2 promotes tumor progression via RICTOR in a serum‑dependent manner, which may be a potential therapeutic target for CRC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Lin SH, Raju GS, Huff C, Ye Y, Gu J, Chen JS, Hildebrandt MAT, Liang H, Menter DG, Morris J, et al: The somatic mutation landscape of premalignant colorectal adenoma. Gut. 67:1299–1305. 2018. View Article : Google Scholar : PubMed/NCBI
3	Marschner N, Zacharias S, Lordick F, Hegewisch-Becker S, Martens U, Welt A, Hagen V, Gleiber W, Bohnet S, Kruggel L, et al: Association of disease progression with health-related quality of life among adults with breast, lung, pancreatic, and colorectal cancer. JAMA Netw Open. 3:e2006432020. View Article : Google Scholar : PubMed/NCBI
4	Chiorean EG, Nandakumar G, Fadelu T, Temin S, Alarcon-Rozas AE, Bejarano S, Croitoru AE, Grover S, Lohar PV, Odhiambo A, et al: Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline. JCO Glob Oncol. 6:414–438. 2020. View Article : Google Scholar : PubMed/NCBI
5	Runge KW and Zakian VA: TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae. Mol Cell Biol. 16:3094–3105. 1996. View Article : Google Scholar : PubMed/NCBI
6	Saxton RA and Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell. 169:361–371. 2017. View Article : Google Scholar : PubMed/NCBI
7	Brown MC and Gromeier M: MNK controls mTORC1: Substrate association through regulation of TELO2 binding with mTORC1. Cell Rep. 18:1444–1457. 2017. View Article : Google Scholar : PubMed/NCBI
8	Takai H, Wang RC, Takai KK, Yang H and de Lange T: Tel2 regulates the stability of PI3K-related protein kinases. Cell. 131:1248–1259. 2007. View Article : Google Scholar : PubMed/NCBI
9	Bahrami A, Khazaei M, Hasanzadeh M, ShahidSales S, Joudi Mashhad M, Farazestanian M, Sadeghnia HR, Rezayi M, Maftouh M, Hassanian SM and Avan A: Therapeutic potential of targeting PI3K/AKT pathway in treatment of colorectal cancer: Rational and progress. J Cell Biochem. 119:2460–2469. 2018. View Article : Google Scholar : PubMed/NCBI
10	Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T and Mizushima N: Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem. 285:20109–20116. 2010. View Article : Google Scholar : PubMed/NCBI
11	Takai H, Xie Y, de Lange T and Pavletich NP: Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes. Genes Dev. 24:2019–2030. 2010. View Article : Google Scholar : PubMed/NCBI
12	Fernandez-Saiz V, Targosz BS, Lemeer S, Eichner R, Langer C, Bullinger L, Reiter C, Slotta-Huspenina J, Schroeder S, Knorn AM, et al: SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma. Nat Cell Biol. 15:72–81. 2013. View Article : Google Scholar : PubMed/NCBI
13	Morais-Rodrigues F, Silv Erio-Machado R, Kato RB, Rodrigues DLN, Valdez-Baez J, Fonseca V, San EJ, Gomes LGR, Dos Santos RG, Vinicius Canário Viana M, et al: Analysis of the microarray gene expression for breast cancer progression after the application modified logistic regression. Gene. 726:1441682020. View Article : Google Scholar : PubMed/NCBI
14	Feng SW, Chen Y, Tsai WC, Chiou HC, Wu ST, Huang LC, Lin C, Hsieh CC, Yang YJ and Hueng DY: Overexpression of TELO2 decreases survival in human high-grade gliomas. Oncotarget. 7:46056–46066. 2016. View Article : Google Scholar : PubMed/NCBI
15	Gala MK, Mizukami Y, Le LP, Moriichi K, Austin T, Yamamoto M, Lauwers GY, Bardeesy N and Chung DC: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology. 146:520–529. 2014. View Article : Google Scholar : PubMed/NCBI
16	Sarbassov DD, Guertin DA, Ali SM and Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 307:1098–1101. 2005. View Article : Google Scholar : PubMed/NCBI
17	Yang G, Murashige DS, Humphrey SJ and James DE: A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep. 12:937–943. 2015. View Article : Google Scholar : PubMed/NCBI
18	Lampada A, O'Prey J, Szabadkai G, Ryan KM, Hochhauser D and Salomoni P: mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism. Cell Death Differ. 24:1045–1062. 2017. View Article : Google Scholar : PubMed/NCBI
19	Wang L, Qi J, Yu J, Chen H, Zou Z, Lin X and Guo L: Overexpression of rictor protein in colorectal cancer is correlated with tumor progression and prognosis. Oncol Lett. 14:6198–6202. 2017.PubMed/NCBI
20	Creytens D: NKX2.2 immunohistochemistry in the distinction of ewing sarcoma from cytomorphologic mimics: Diagnostic utility and pitfalls-comment on russell-goldman et al. Cancer Cytopathol. 127:2022019. View Article : Google Scholar : PubMed/NCBI
21	Zhao Y, Zhang W, Guo Z, Ma F, Wu Y, Bai Y, Gong W, Chen Y, Cheng T, Zhi F, et al: Inhibition of the transcription factor Sp1 suppresses colon cancer stem cell growth and induces apoptosis in vitro and in nude mouse xenografts. Oncol Rep. 30:1782–1792. 2013. View Article : Google Scholar : PubMed/NCBI
22	Chen Y, Liu J, Wang W, Xiang L, Wang J, Liu S, Zhou H and Guo Z: High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer. Oncol Rep. 39:1693–1701. 2018.PubMed/NCBI
23	Park SJ, Yoon BH, Kim SK and Kim SY: GENT2: An updated gene expression database for normal and tumor tissues. BMC Med Genomics. 12 (Suppl 5):S1012019. View Article : Google Scholar
24	Carroll B: Spatial regulation of mTORC1 signalling: Beyond the Rag GTPases. Semin Cell Dev Biol. 107:103–111. 2020. View Article : Google Scholar : PubMed/NCBI
25	Rabanal-Ruiz Y and Korolchuk VI: mTORC1 and nutrient homeostasis: The central role of the lysosome. Int J Mol Sci. 19:8182018. View Article : Google Scholar
26	Li X and Gao T: mTORC2 phosphorylates protein kinase Cζ to regulate its stability and activity. EMBO Rep. 15:191–198. 2014. View Article : Google Scholar : PubMed/NCBI
27	Knudsen JR, Fritzen AM, James DE, Jensen TE, Kleinert M and Richter EA: Growth factor-dependent and -independent activation of mTORC2. Trends Endocrinol Metab. 31:13–24. 2020. View Article : Google Scholar : PubMed/NCBI
28	Manning BD and Toker A: AKT/PKB signaling: Navigating the network. Cell. 169:381–405. 2017. View Article : Google Scholar : PubMed/NCBI
29	Jia R and Bonifacino JS: Lysosome positioning influences mTORC2 and AKT signaling. Mol Cell. 75:26–38.e3. 2019. View Article : Google Scholar : PubMed/NCBI
30	Zhao J, Zhai B, Gygi SP and Goldberg AL: mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci USA. 112:15790–15797. 2015. View Article : Google Scholar : PubMed/NCBI
31	Gkountakos A, Pilotto S, Mafficini A, Vicentini C, Simbolo M, Milella M, Tortora G, Scarpa A, Bria E and Corbo V: Unmasking the impact of Rictor in cancer: Novel insights of mTORC2 complex. Carcinogenesis. 39:971–980. 2018. View Article : Google Scholar : PubMed/NCBI
32	Zhang S, Qian G, Zhang QQ, Yao Y, Wang D, Chen ZG, Wang LJ, Chen M and Sun SY: mTORC2 suppresses GSK3-dependent snail degradation to positively regulate cancer cell invasion and metastasis. Cancer Res. 79:3725–3736. 2019. View Article : Google Scholar : PubMed/NCBI
33	Serrano I, McDonald PC, Lock FE and Dedhar S: Role of the integrin-linked kinase (ILK)/Rictor complex in TGFβ-1-induced epithelial-mesenchymal transition (EMT). Oncogene. 32:50–60. 2013. View Article : Google Scholar : PubMed/NCBI
34	Pan SJ, Zhan SK, Pan YX, Liu W, Bian LG, Sun B and Sun QF: Tetraspanin 8-rictor-integrin α3 complex is required for glioma cell migration. Int J Mol Sci. 16:5363–5374. 2015. View Article : Google Scholar : PubMed/NCBI
35	Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, et al: Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell. 39:797–808. 2010. View Article : Google Scholar : PubMed/NCBI
36	Guo Z, Zhou Y, Evers BM and Wang Q: Rictor regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells. Biochem Biophys Res Commun. 418:426–432. 2012. View Article : Google Scholar : PubMed/NCBI