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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2

Authors: Shan Li, Yan-Min Ma, Peng-Sheng Zheng, Ping Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported.

Methods

Immunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2.

Results

GDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells.

Conclusions

Our data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.
Appendix
Available only for authorised users
Literature
1.
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
2.
Narisawa-Saito M, Kiyono T. Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 2007;98:1505–11.CrossRefPubMed
3.
Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550–60.CrossRefPubMed
4.
5.
Liu XF, Li XY, Zheng PS, et al. DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/beta-catenin pathway via GSK3beta. Cell Death Dis. 2018;9:339.CrossRefPubMedPubMedCentral
6.
Yang WT, Zheng PS. Kruppel-like factor 4 functions as a tumor suppressor in cervical carcinoma. Cancer. 2012;118:3691–702.CrossRefPubMed
7.
Cui N, Yang WT, Zheng PS. Slug inhibits the proliferation and tumor formation of human cervical cancer cells by up-regulating the p21/p27 proteins and down-regulating the activity of the Wnt/beta-catenin signaling pathway via the trans-suppression Akt1/p-Akt1 expression. Oncotarget. 2016;7:26152–67.PubMedPubMedCentral
8.
Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-beta family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev. 2013;24:373–84.CrossRefPubMed
9.
Mimeault M, Batra SK. Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer. J Cell Physiol. 2010;224:626–35.CrossRefPubMedPubMedCentral
10.
Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12:104–7.CrossRefPubMed
11.
Yang CZ, Ma J, Zhu DW, et al. GDF15 is a potential predictive biomarker for TPF induction chemotherapy and promotes tumorigenesis and progression in oral squamous cell carcinoma. Ann Oncol. 2014;25:1215–22.CrossRefPubMed
12.
Wan F, Miao X, Quraishi I, et al. Gene expression changes during HPV-mediated carcinogenesis: a comparison between an in vitro cell model and cervical cancer. Int J Cancer. 2008;123:32–40.CrossRefPubMedPubMedCentral
13.
14.
15.
Zajac-Kaye M. Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer. Lung Cancer. 2001;34(Suppl 2):S43–6.CrossRefPubMed
16.
Hwang-Verslues WW, Sladek FM. Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter. Mol Endocrinol. 2008;22:78–90.CrossRefPubMed
17.
Roy SK, Srivastava RK, Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 2010;5:10.CrossRefPubMedPubMedCentral
18.
Zhao Q, Assimopoulou AN, Klauck SM, et al. Inhibition of c-MYC with involvement of ERK/JNK/MAPK and AKT pathways as a novel mechanism for shikonin and its derivatives in killing leukemia cells. Oncotarget. 2015;6:38934–51.PubMedPubMedCentral
19.
Kim KK, Lee JJ, Yang Y, et al. Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells. Carcinogenesis. 2008;29:704–12.CrossRefPubMed
20.
Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282–303.CrossRefPubMedPubMedCentral
21.
Avraham R, Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol. 2011;12:104–17.CrossRefPubMed
22.
23.
Li C, Wang Q, Wang JF. Transforming growth factor-beta (TGF-beta) induces the expression of chondrogenesis-related genes through TGF-beta receptor II (TGFRII)-AKT-mTOR signaling in primary cultured mouse precartilaginous stem cells. Biochem Biophys Res Commun. 2014;450:646–51.CrossRefPubMed
24.
Welsh JB, Sapinoso LM, Kern SG, et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci U S A. 2003;100:3410–5.CrossRefPubMedPubMedCentral
25.
Chen SJ, Karan D, Johansson SL, et al. Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells. Prostate. 2007;67:557–71.CrossRefPubMed
26.
Boyle GM, Pedley J, Martyn AC, et al. Macrophage inhibitory cytokine-1 is overexpressed in malignant melanoma and is associated with tumorigenicity. J Invest Dermatol. 2009;129:383–91.CrossRefPubMed
27.
Griner SE, Joshi JP, Nahta R. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion. Biochem Pharmacol. 2013;85:46–58.CrossRefPubMed
28.
Wang X, Li Y, Tian H, et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer. 2014;14:578.CrossRefPubMedPubMedCentral
29.
Mehta RS, Chong DQ, Song M, et al. Association between plasma levels of macrophage inhibitory cytokine-1 before diagnosis of colorectal cancer and mortality. Gastroenterology. 2015;149:614–22.CrossRefPubMedPubMedCentral
30.
Joshi JP, Brown NE, Griner SE, et al. Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells. Biochem Pharmacol. 2011;82:1090–9.CrossRefPubMedPubMedCentral
31.
Wallin U, Glimelius B, Jirstrom K, et al. Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer. Br J Cancer. 2011;104:1619–27.CrossRefPubMedPubMedCentral
32.
Tsui KH, Chang YL, Feng TH, et al. Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells. J Mol Endocrinol. 2012;49:153–63.CrossRefPubMed
33.
Jin YJ, Lee JH, Kim YM, et al. Macrophage inhibitory cytokine-1 stimulates proliferation of human umbilical vein endothelial cells by up-regulating cyclins D1 and E through the PI3K/Akt-, ERK-, and JNK-dependent AP-1 and E2F activation signaling pathways. Cell Signal. 2012;24:1485–95.CrossRefPubMed
34.
Boreddy SR, Pramanik KC, Srivastava SK. Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin Cancer Res. 2011;17:1784–95.CrossRefPubMedPubMedCentral
35.
Yamagata K, Daitoku H, Takahashi Y, et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell. 2008;32:221–31.CrossRefPubMed
36.
Xin B, Yamamoto M, Fujii K, et al. Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways. Oncogene. 2017;36:5087-97
37.
Pan CC, Bloodworth JC, Mythreye K, et al. Endoglin inhibits ERK-induced c-Myc and cyclin D1 expression to impede endothelial cell proliferation. Biochem Biophys Res Commun. 2012;424:620–3.CrossRefPubMedPubMedCentral
38.
Shankar S, Chen Q, Srivastava RK. Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor. J Mol Signal. 2008;3:7.CrossRefPubMedPubMedCentral
39.
Yang L, Chang CC, Sun Z, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017;23:1158–66.CrossRefPubMed
40.
Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23:1215–9.CrossRefPubMed
41.
Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23:1150–7.CrossRefPubMed
Metadata
Title
GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2
Authors
Shan Li
Yan-Min Ma
Peng-Sheng Zheng
Ping Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0744-0

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Review

Relevance of 3d culture systems to study osteosarcoma environment

Research

The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model

Correction

Correction to: RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1

Research

BRD7 expression and c-Myc activation forms a double-negative feedback loop that controls the cell proliferation and tumor growth of nasopharyngeal carcinoma by targeting oncogenic miR-141

Commentary

Iron-dependent cell death as executioner of cancer stem cells

Review

Emerging role of lipid metabolism alterations in Cancer stem cells
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