Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells

  • Authors:
    • Peng Zhang
    • Zengshu Xing
    • Xuechao Li
    • Yarong Song
    • Jun Zhao
    • Yajun Xiao
    • Yifei Xing
  • View Affiliations

  • Published online on: January 25, 2016     https://doi.org/10.3892/ijo.2016.3356
  • Pages: 1417-1425
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Renal cell carcinoma (RCC) is the most common solid neoplasm of adult kidney, and the major treatment for metastatic RCC (mRCC) is molecular targeted therapy. Sorafenib, as a multi-targeted tyrosine kinase inhibitor (TKI), has significantly improved clinical outcomes of mRCC patients. However, complete or long-term remissions are rarely achieved due to intolerance to dose-related adverse effects. It is therefore, necessary to explore novel target molecules for treatment or to enhance the therapeutic efficiency of present TKI for mRCC treatment. Anoikis is a specific type of apoptosis that plays a vital physiological role in regulating tissue homoeostasis. Anoikis-resistance is of critical importance for metastasis of various human cancers including mRCC. However, the precise mechanisms on anoikis-resistance in mRCC are still unclear. Tyrosine receptor kinase B (TrkB) belongs to the Trk family of neurotrophin receptors. Previous investigations have implied that activation or overexpression of TrkB promoted proliferation, survival, angiogenesis, anoikis-resistance and metastasis in human cancers. Yet, the correlation between TrkB and anoikis-resistance in mRCC has rarely been reported. The aim of the present study was to explore the impact of TrkB on anoikis-resistance and targeted therapy in mRCC. Our data revealed that anoikis-resistant ACHN cells presented with tolerance to detachment-induced apoptosis, excessive proliferation and aggressive invasion, accompanied by upregulation of TrkB expression in contrast to parental cells. Furthermore, TrkB silencing caused apoptosis, inhibited proliferation, retarded invasion as well as improved anticancer efficiency of sorafenib in anoikis-resistant ACHN cells through inactivation of PI3K/Akt and MEK/ERK pathways. Our data may offer a novel potential therapeutic strategy for mRCC.

References

1 

Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S and Kiemeney LA: The epidemiology of renal cell carcinoma. Eur Urol. 60:615–621. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Kim DY, Karam JA and Wood CG: Role of metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy. World J Urol. 32:631–642. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Ridge CA, Pua BB and Madoff DC: Epidemiology and staging of renal cell carcinoma. Semin Intervent Radiol. 31:3–8. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 24:2505–2512. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Zustovich F, Lombardi G, Pastorelli D, Farina P, Bianco MD, De Zorzi L, Palma MD, Nicoletto O and Zagonel V: Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma. Open Access J Urol. 3:69–82. 2011.PubMed/NCBI

6 

Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356:125–134. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Bianchi L, Rossi L, Tomao F, Papa A, Zoratto F and Tomao S: Thyroid dysfunction and tyrosine kinase inhibitors in renal cell carcinoma. Endocr Relat Cancer. 20:R233–R245. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Chiarugi P and Giannoni E: Anoikis: A necessary death program for anchorage-dependent cells. Biochem Pharmacol. 76:1352–1364. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Zhong X and Rescorla FJ: Cell surface adhesion molecules and adhesion-initiated signaling: Understanding of anoikis resistance mechanisms and therapeutic opportunities. Cell Signal. 24:393–401. 2012. View Article : Google Scholar

10 

Simpson CD, Anyiwe K and Schimmer AD: Anoikis resistance and tumor metastasis. Cancer Lett. 272:177–185. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Jenning S, Pham T, Ireland SK, Ruoslahti E and Biliran H: Bit1 in anoikis resistance and tumor metastasis. Cancer Lett. 333:147–151. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Bouillez A, Gnemmi V, Gaudelot K, Hémon B, Ringot B, Pottier N, Glowacki F, Butruille C, Cauffiez C, Hamdane M, et al: MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway. Oncotarget. 5:754–763. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Sakamoto S, Schwarze S and Kyprianou N: Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma. Eur Urol. 59:734–744. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Stoilov P, Castren E and Stamm S: Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun. 290:1054–1065. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M and Yancopoulos GD: TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor. Cell. 66:405–413. 1991. View Article : Google Scholar : PubMed/NCBI

16 

Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E and Peeper DS: Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 430:1034–1039. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Thiele CJ, Li Z and McKee AE: On Trk - the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res. 15:5962–5967. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Lam CT, Yang ZF, Lau CK, Tam KH, Fan ST and Poon RT: Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: implication in hepatocellular carcinoma. Clin Cancer Res. 17:3123–3133. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Sinkevicius KW, Kriegel C, Bellaria KJ, Lee J, Lau AN, Leeman KT, Zhou P, Beede AM, Fillmore CM, Caswell D, et al: Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis. Proc Natl Acad Sci USA. 111:10299–10304. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Fujikawa H, Tanaka K, Toiyama Y, Saigusa S, Inoue Y, Uchida K and Kusunoki M: High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells. J Gastroenterol. 47:775–784. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Sclabas GM, Fujioka S, Schmidt C, Li Z, Frederick WA, Yang W, Yokoi K, Evans DB, Abbruzzese JL, et al: Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res. 11:440–449. 2005.PubMed/NCBI

22 

Mawji IA, Simpson CD, Hurren R, Gronda M, Williams MA, Filmus J, Jonkman J, Da Costa RS, Wilson BC, Thomas MP, et al: Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation. J Natl Cancer Inst. 99:811–822. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Fidler IJ: The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003. View Article : Google Scholar : PubMed/NCBI

24 

Geiger TR and Peeper DS: The neurotrophic receptor TrkB in anoikis resistance and metastasis: A perspective. Cancer Res. 65:7033–7036. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Liotta LA and Kohn E: Anoikis: Cancer and the homeless cell. Nature. 430:973–974. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Wong KK, Engelman JA and Cantley LC: Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev. 20:87–90. 2010. View Article : Google Scholar :

27 

Montagut C and Settleman J: Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett. 283:125–134. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Frisch SM and Screaton RA: Anoikis mechanisms. Curr Opin Cell Biol. 13:555–562. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Shih YW, Shieh JM, Wu PF, Lee YC, Chen YZ and Chiang TA: Alpha-tomatine inactivates PI3K/Akt and ERK signaling pathways in human lung adenocarcinoma A549 cells: effect on metastasis. Food Chem Toxicol. 47:1985–1995. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Wongpankam E, Chunhacha P, Pongrakhananon V, Sritularak B and Chanvorachote P: Artonin E mediates MCL1 down-regulation and sensitizes lung cancer cells to anoikis. Anticancer Res. 32:5343–5351. 2012.PubMed/NCBI

31 

Klein R, Nanduri V, Jing SA, Lamballe F, Tapley P, Bryant S, Cordon-Cardo C, Jones KR, Reichardt LF and Barbacid M: The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 66:395–403. 1991. View Article : Google Scholar : PubMed/NCBI

32 

Pearse RN, Swendeman SL, Li Y, Rafii D and Hempstead BL: A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood. 105:4429–4436. 2005. View Article : Google Scholar

33 

Yu X, Liu L, Cai B, He Y and Wan X: Suppression of anoikis by the neurotrophic receptor TrkB in human ovarian cancer. Cancer Sci. 99:543–552. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Smit MA and Peeper DS: Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis. Oncogene. 30:3735–3744. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Ramnath N and Adjei A: Inhibitors of Raf kinase and MEK signaling. Update Cancer Ther. 2:111–118. 2007. View Article : Google Scholar

36 

Kim MJ, Kim DE, Jeong IG, Choi J, Jang S, Lee JH, Ro S, Hwang JJ and Kim CS: HDAC inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma cells. Anticancer Res. 32:3161–3168. 2012.PubMed/NCBI

37 

Srikanthan A, Ethier JL, Ocana A, Seruga B, Krzyzanowska MK and Amir E: Cardiovascular toxicity of multi-tyrosine kinase inhibitors in advanced solid tumors: A population-based observational study. PLoS One. 10:e01227352015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April 2016
Volume 48 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhang, P., Xing, Z., Li, X., Song, Y., Zhao, J., Xiao, Y., & Xing, Y. (2016). Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells. International Journal of Oncology, 48, 1417-1425. https://doi.org/10.3892/ijo.2016.3356
MLA
Zhang, P., Xing, Z., Li, X., Song, Y., Zhao, J., Xiao, Y., Xing, Y."Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells". International Journal of Oncology 48.4 (2016): 1417-1425.
Chicago
Zhang, P., Xing, Z., Li, X., Song, Y., Zhao, J., Xiao, Y., Xing, Y."Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells". International Journal of Oncology 48, no. 4 (2016): 1417-1425. https://doi.org/10.3892/ijo.2016.3356