Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 8/2014

01-12-2014 | Research Paper

TGFβ can stimulate the p38/β-catenin/PPARγ signaling pathway to promote the EMT, invasion and migration of non-small cell lung cancer (H460 cells)

Authors: Li-Chiung Lin, Shih-Lan Hsu, Chieh-Liang Wu, Chi-Mei Hsueh

Published in: Clinical & Experimental Metastasis | Issue 8/2014

Login to get access

Abstract

Signaling pathway(s) responsible for transforming growth factor β (TGFβ)-induced epithelial mesenchymal transition (EMT), invasion and migration of H460 cells (non-small cell lung cancer/NSCLC) was identified in the study. The results showed that TGFβ-induced p38/β-catenin/PPARγ signaling pathway played a critical role in the promotion of EMT, invasion and migration of H460 cells. All these pathological outcomes attributed to PPARγ-increased expression of p-EGFR, p-c-MET and Vimentin and the decrease of E-cadherin. Transforming growth factor β and p38-induced β-catenin not only stimulated the expression of PPARγ but also physically interacted with it. Blocking the ligand binding domain of PPARγ (with GW9662) could significantly interfere the binding between PPARγ and β-catenin, and interrupt the nuclear infiltration of both factors. These findings suggested that β-catenin was an upstream regulator and a ligand of PPARγ, and the binding between these two molecules was critical for their nuclear infiltration. Transforming growth factor β-induced tumor invasion and migration was also seen in U373 cells (brain glioma, with high inducible PPARγ) in a PPARγ-dependent manner, but not in CH27 cells (squamous NSCLC, with low PPARγ). PPARγ shRNA, GW9662, JW67 and 2,4-diaminoquinazoline were all revealed to have important values in the control of the intrinsic and TGFβ-induced EMT, tumor invasion and migration of H460 cells. The results further suggested that PPARγ and β-catenin may be the potential markers for the early diagnosis and/or treatment of metastatic tumors.
Literature
1.
Bennett WP, el-Deiry WS, Rush WL, Guinee DG Jr, Freedman AN, Caporaso NE, Welsh JA, Jones RT, Borkowski A, Travis WD, Fleming MV, Trastek V, Pairolero PC, Tazelaar HD, Midthun D, Jett JR, Liotta LA, Harris CC (1998) p21waf1/cip1 and transforming growth factor β1 protein expression correlate with survival in non-small cell lung cancer. Clin Cancer Res 4:1499–1506PubMed
2.
Bikkavilli RK, Feigin ME, Malbon CC (2008) p38 mitogen-activated protein kinase regulates canonical Wnt-β-catenin signaling by inactivation of GSK3β. J Cell Sci 121:3598–3607PubMedCrossRef
3.
Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, Kirchner T (2005) Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and β-catenin. Cells Tissues Organs 179:56–65PubMedCrossRef
4.
Bren-Mattison Y, Van Putten V, Chan D, Winn R, Geraci MW, Nemenoff RA (2005) Peroxisome proliferators-activated receptor γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 24:1412–1422PubMedCrossRef
5.
Chen Z, Venkatesan AM, Dehnhardt CM, Dos Santos O, Delos Santos E, Ayral-Kaloustian S, Chen L, Geng Y, Arndt KT, Lucas J, Chaudhary I, Mansour TS (2009) 2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: potential treatment for colorectal cancer. Bioorg Med Chem Lett 19:4980–4983PubMedCrossRef
6.
Choi IK, Kim YH, Kim JS, Seo JH (2008) PPARγ ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo. Invest New Drugs 26:283–288PubMedCrossRef
7.
Chow G, Tauler J, Mulshine JL (2010) Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer. J Biomed Biotechnol 2010:485468PubMedCentralPubMedCrossRef
8.
DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA (1998) The nuclear eicosanoid receptor, PPARγ, is aberrantly expressed in colonic cancers. Carcinogenesis 19:49–53PubMedCrossRef
9.
Eger A, Stockinger A, Park J, Langkopf E, Mikula M, Gotzmann J, Mikulits W, Beug H, Foisner R (2004) β-catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23:2672–2680PubMedCrossRef
10.
Endo Y, Suzuki M, Hamada H, Horita S, Kunimi M, Yamazaki O, Shirai A, Nakamura M, Iso-O N, Li Y, Hara M, Tsukamoto K, Moriyama N, Kudo A, Kawakami H, Yamauchi T, Kubota N, Kadowaki T, Kume H, Enomoto Y, Homma Y, Seki G, Fujita T (2011) Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling. Cell Metab 13:550–561PubMedCrossRef
11.
Fischer AN, Herrera B, Mikula M, Proell V, Fuchs E, Gotzmann J, Schulte-Hermann R, Beug H, Mikulits W (2005) Integration of Ras subeffector signaling in TGFβ mediated late stage hepatocarcinogenesis. Carcinogenesis 26:931–942PubMedCrossRef
12.
Giaginis C, Politi E, Alexandrou P, Sfiniadakis J, Kouraklis G, Theocharis S (2012) Expression of Peroxisome proliferator activated receptor-gamma (PPAR-γ) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients’ survival. Pathol Oncology Res 18:875–883
13.
Girnun GD, Chen L, Silvaggi J, Drapkin R, Chirieac LR, Padera RF, Upadhyay R, Vafai SB, Weissleder R, Mahmood U, Naseri E, Buckley S, Li D, Force J, McNamara K, Demetri G, Spiegelman BM, Wong KK (2008) Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin Cancer Res 14:6478–6486PubMedCentralPubMedCrossRef
14.
Guo A, Villén J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R, Wang Y, MacNeill J, Mitchell J, Gygi SP, Rush J, Polakiewicz RD, Comb MJ (2008) Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105:692–697PubMedCentralPubMedCrossRef
15.
Han C, Demetris AJ, Liu Y, Shelhamer JH, Wu T (2004) Transforming growth factor β (TGFβ) activates cytosolic phospholipase A2α (cPLA2α)-mediated prostaglandin E2 (PGE2)/EP1 and peroxisome proliferator-activated receptor γ (PPARγ)/Smad signaling pathways in human liver cancer cells. J Biol Chem 279:44344–44354PubMedCrossRef
16.
Han C, Michalopoulos GK, Wu T (2006) Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J Cell Physiol 207:261–270PubMedCrossRef
17.
Hasegawa Y, Takanashi S, Kanehira Y, Tsushima T, Imai T, Okumura K (2001) Transforming growth factor β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with non small cell lung carcinoma. Cancer 91:964–971PubMedCrossRef
18.
Hoshiba T, Kawazoe N, Tateishi T, Chen G (2009) Development of stepwise osteogenesis-mimicking matrices for the regulation of mesenchymal stem cell functions. J Biol Chem 284:31164–31173PubMedCentralPubMedCrossRef
19.
Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grünert S (2002) Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313PubMedCentralPubMedCrossRef
20.
Jansson EA, Are A, Greicius G, Kuo IC, Kelly D, Arulampalam V, Pettersson S (2005) The Wnt/β-catenin signaling pathway targets PPARγ activity in colon cancer cells. Proc Natl Acad Sci USA 102:1460–1465PubMedCentralPubMedCrossRef
21.
Keshamouni VG, Reddy RC, Arenberg DA, Joel B, Thannickal VJ, Kalemkerian GP, Standiford TJ (2004) Peroxisome proliferators-activated receptor γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 23:100–108PubMedCrossRef
22.
Kim ES, Kim MS, Moon A (2005) Transforming growth factor (TGF) β in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine 29:84–91PubMedCrossRef
23.
Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, Davis RG, Hull-Ryde EA, Lenhard JM, Patel L, Plunket KD, Shenk JL, Stimmel JB, Therapontos C, Willson TM, Blanchard SG (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41:6640–6650PubMedCrossRef
24.
Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J (1998) Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 4:1053–1057PubMedCrossRef
25.
Lin LC, Hsu SL, Wu CL, Liu WC, Hsueh CM (2011) Peroxisome proliferator-activated receptor γ (PPARγ) plays a critical role in the development of TGFβ resistance of H460 cell. Cell Signal 23:1640–1650PubMedCrossRef
26.
Liu M, Yang SC, Sharma S, Luo J, Cui X, Peebles KA, Huang M, Sato M, Ramirez RD, Shay JW, Minna JD, Dubinett SM (2007) EGFR signaling is required for TGFβ1 mediated COX-2 induction in human bronchial epithelial cells. Am J Respir Cell Mol Biol 37:578–588PubMedCentralPubMedCrossRef
27.
López-González JS, Aguilar-Cázares D, Prado-García H, Nieto-Rodríguez A, Mandoki JJ, Avila-Moreno F, Rivera RM, Chavarría-Garcés J (2002) Lack of correlation between growth inhibition by TGFβ receptor in human non-small cell lung cacinoma cell lines. Lung Cancer 38:149–158PubMedCrossRef
28.
29.
30.
Navab R, Liu J, Seiden-Long I, Shih W, Li M, Bandarchi B, Chen Y, Lau D, Zu YF, Cescon D, Zhu CQ, Organ S, Ibrahimov E, Ohanessian D, Tsao MS (2009) Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. Neoplasia 11:1292–1300PubMedCentralPubMed
31.
Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E (1996) TGFβ and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10:2462–2477PubMedCrossRef
32.
Oft M, Heider KH, Beug H (1998) TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243–1252PubMedCrossRef
33.
Ohta T, Elnemr A, Yamamoto M, Ninomiya I, Fushida S, Nishimura G, Fujimura T, Kitagawa H, Kayahara M, Shimizu K, Yi S, Miwa K (2002) Thiazolidinedione, a peroxisome proliferator-activated receptor ligand, modulates the E-cadherin/β-catenin system in a human pancreatic cancer cell line, BxPC-3. Int J Oncol 21:37–42PubMed
34.
35.
36.
Reka AK, Kurapati H, Narala VR, Bommer G, Chen J, Standiford TJ, Keshamouni VG (2010) Peroxisome proliferator-activated receptor γ activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition. Mol Cancer Ther 9:3221–3232PubMedCentralPubMedCrossRef
37.
Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, Kim CH, Lee J (2009) Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EFGR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer 63:219–226
38.
Saez E, Rosenfeld J, Livolsi A, Olson P, Lombardo E, Nelson M, Banayo E, Cardiff RD, Izpisua-Belmonte JC, Evans RM (2004) PPARγ signaling exacerbates mammary gland tumor development. Genes Dev 18:528–540PubMedCentralPubMedCrossRef
39.
Sauvant P, Cansell M, Atgié C (2011) Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes. J Physiol Biochem 67:487–496PubMedCrossRef
40.
Sharma C, Pradeep A, Wong L, Rana A, Rana B (2004) Peroxisome proliferator-activated receptor γ activation can regulate β-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway. J Biol Chem 279:35583–35594PubMedCrossRef
41.
Sibani S, Price GB, Zannis-Hadjopoulos M (2005) Decreased origin usage and initiation of DNA replication in haploinsufficient HCT116 Ku80+/− cells. J Cell Sci 118:3247–3261PubMedCrossRef
42.
Smith AG, Beaumont KA, Smit DJ, Thurber AE, Cook AL, Boyle GM, Parsons PG, Sturm RA, Muscat GE (2009) PPARγ agonists attenuate proliferation and modulate Wnt/β-catenin signalling in melanoma cells. Int J Biochem Cell Biol 41:844–852PubMedCrossRef
43.
44.
Theocharis S, Kanelli H, Politi E, Margeli A, Karkandaris C, Philippides T, Koutselinis A (2002) Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade. Lung Cancer 36:249–255
45.
Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3β inactivation. Science 320:667–670PubMedCentralPubMedCrossRef
46.
Tymianski M, Charlton MP, Carlen PL, Tator CH (1993) Secondary Ca2+ overload indicates early neuronal injury which precedes staining with viability indicators. Brain Res 607:319–323PubMedCrossRef
47.
Waaler J, Machon O, von Kries JP, Wilson SR, Lundenes E, Wedlich D, Gradl D, Paulsen JE, Machonova O, Dembinski JL, Dinh H, Krauss S (2011) Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res 71:197–205PubMedCrossRef
48.
Wang XQ, Li H, Van Putten V, Winn RA, Heasley LE, Nemenoff RA (2009) Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9. Mol Biol Cell 20:791–800PubMedCentralPubMedCrossRef
49.
Yoshizumi T, Ohta T, Ninomiya I, Terada I, Fushida S, Fujimura T, Nishimura G, Shimizu K, Yi S, Miwa K (2004) Thiazolidinedione, a peroxisome proliferator-activated receptor γ ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Oncol 25:631–639PubMed
50.
Yuan Y, Zhang A, Huang S, Ding G, Chen R (2011) A PPARγ agonist inhibits aldosterone-induced mesangial cell proliferation by blocking ROS-dependent EGFR intracellular signaling. Am J Physiol Renal Physiol 300:F393–F402PubMedCrossRef
Metadata
Title
TGFβ can stimulate the p38/β-catenin/PPARγ signaling pathway to promote the EMT, invasion and migration of non-small cell lung cancer (H460 cells)
Authors
Li-Chiung Lin
Shih-Lan Hsu
Chieh-Liang Wu
Chi-Mei Hsueh
Publication date
01-12-2014
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 8/2014
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-014-9677-y

Other articles of this Issue 8/2014

Clinical & Experimental Metastasis 8/2014 Go to the issue

Research Paper

A role for STEAP2 in prostate cancer progression

OriginalPaper

Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer

OriginalPaper

Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading

OriginalPaper

Placenta-breast cancer cell interactions promote cancer cell epithelial mesenchymal transition via TGFβ/JNK pathway

Research Paper

CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis

Research Paper

Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK–NF-κB signaling pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits