Mammalian sterile-like 1 kinase inhibits TGFβ and EGF‑dependent regulation of invasiveness, migration and proliferation of HEC-1-A endometrial cancer cells

Attarha,Sanaz; Andersson,Sonia; Mints,Miriam; Souchelnytskyi,Serhiy

doi:10.3892/ijo.2014.2447

Mammalian sterile-like 1 kinase inhibits TGFβ and EGF‑dependent regulation of invasiveness, migration and proliferation of HEC-1-A endometrial cancer cells

Authors:
- Sanaz Attarha
- Sonia Andersson
- Miriam Mints
- Serhiy Souchelnytskyi
View Affiliations

Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SE-17176, Sweden, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-17176, Sweden
Published online on: May 19, 2014 https://doi.org/10.3892/ijo.2014.2447
Pages: 853-860

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Transforming growth factor-β (TGFβ) and epidermal growth factor (EGF) are two potent regulators of tumorigenesis. Signaling cross-talk of TGFβ and EGF employs a number of regulators which define the impact on cell physiology. MST1 has recently been reported as a regulator of tumorigenesis and differentiation. To investigate the role of mammalian sterile-like 1 (MST1) in TGFβ and EGF signaling, we established transiently MST1‑transfected HEC-1-A endometrial cancer cells, and subjected the cells to treatment with TGFβ1, EGF and their combination. We report MST1 as a negative regulator of combined TGFβ and EGF signaling. We observed that enhanced expression of MST1 inhibited the combined action of TGFβ1 and EGF on cell invasiveness, migration and proliferation. Monitoring of the intracellular regulatory proteins showed that MST1 contribution to the TGFβ-EGF cross-talk may involve focal adhesion kinase and E-cadherin, but not activation of Smad2. Our data unveiled the role of MST1 as a negative feedback for TGFβ1‑ and EGF‑regulated cell invasiveness, migration and proliferation.

View Figures

View References

1	Jakowlew SB: Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 25:435–457. 2006. View Article : Google Scholar : PubMed/NCBI
2	Dunfield LD and Nachtigal MW: Inhibition of the antiproliferative effect of TGFbeta by EGF in primary human ovarian cancer cells. Oncogene. 22:4745–4751. 2003. View Article : Google Scholar
3	Scaltriti M and Baselga J: The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 12:5268–5272. 2006. View Article : Google Scholar : PubMed/NCBI
4	Lurje G and Lenz H-J: EGFR signaling and drug discovery. Oncology. 77:400–410. 2009. View Article : Google Scholar : PubMed/NCBI
5	Creasy CL and Chernoff J: Cloning and characterization of a member of the MST subfamily of Ste20-like kinases. Gene. 167:303–306. 1995. View Article : Google Scholar : PubMed/NCBI
6	Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR and Lugli A: Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod Pathol. 20:331–338. 2007. View Article : Google Scholar : PubMed/NCBI
7	Cinar B, Collak FK, Lopez D, et al: MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling. Cancer Res. 71:4303–4313. 2011. View Article : Google Scholar
8	Steinmann K, Sandner A, Schagdarsurengin U and Dammann RH: Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep. 22:1519–1526. 2009.PubMed/NCBI
9	Seidel C, Schagdarsurengin U, Blümke K, et al: Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog. 46:865–871. 2007. View Article : Google Scholar : PubMed/NCBI
10	Qiao M, Wang Y, Xu X, et al: Mst1 is an interacting protein that mediates PHLPPs’ induced apoptosis. Mol Cell. 38:512–523. 2010.PubMed/NCBI
11	Song H, Mak KK, Topol L, et al: Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA. 107:1431–1436. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gebäck T, Schulz MMP, Koumoutsakos P and Detmar M: TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays. Biotechniques. 46:265–274. 2009.PubMed/NCBI
13	Schneider CA, Rasband WS and Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 9:671–675. 2012.PubMed/NCBI
14	Attarha S, Andersson S, Mints M and Souchelnytskyi S: Individualised proteome profiling of human endometrial tumours improves detection of new prognostic markers. Br J Cancer. 109:704–713. 2013. View Article : Google Scholar : PubMed/NCBI
15	Bi W, Xiao L, Jia Y, et al: c-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82. J Biol Chem. 285:6259–6264. 2010. View Article : Google Scholar : PubMed/NCBI
16	Souchelnytskyi S, Tamaki K, Engström U, Wernstedt C, ten Dijke P and Heldin CH: Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem. 272:28107–28115. 1997. View Article : Google Scholar : PubMed/NCBI
17	Qin F, Tian J, Zhou D and Chen L: Mst1 and Mst2 kinases: regulations and diseases. Cell Biosci. 3:312013. View Article : Google Scholar : PubMed/NCBI
18	Ng Y-K, Lau W-S, Lui VWY, et al: Full-length Mst1 exhibits growth promoting function in human hepatocellular carcinoma cells. FEBS Lett. 587:496–503. 2013. View Article : Google Scholar : PubMed/NCBI
19	Katsuno T, Ochi M, Tominaga K, et al: Mesenchymal stem cells administered in the early phase of tumorigenesis inhibit colorectal tumor development in rats. J Clin Biochem Nutr. 53:170–175. 2013. View Article : Google Scholar : PubMed/NCBI
20	Massagué J: TGF-β signaling in development and disease. FEBS Lett. 586:18332012.
21	Graves JD, Gotoh Y, Draves KE, et al: Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J. 17:2224–2234. 1998. View Article : Google Scholar : PubMed/NCBI
22	Lin Y, Khokhlatchev A, Figeys D and Avruch J: Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis. J Biol Chem. 277:47991–8001. 2002. View Article : Google Scholar : PubMed/NCBI