Skip to main content

Advertisement

SpringerLink
Log in

Ghrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of progression of cancer, especially in metastasis and proliferation. However, the precise role of Ghrelin in tumorigenesis of gastric cancer (GC) is still poorly understood. In this study, we extensively investigated the roles and mechanisms of Ghrelin in human gastric cancer. Ghrelin levels in cancer tissues and cell lines were analyzed by immunohistochemistry, qRT-PCR, and Western blot. Functional studies were performed after Ghrelin overexpressed or knockdown in AGS cell line. Cell proliferation was evaluated in by MTT and clone formation assays. The wound healing and Transwell system were used to assess the cell migration and invasive ability of GC cells. Cell apoptosis was detected by flow cytometry, and metabolic assays were performed to reveal the function of Warburg effect in the process. Ghrelin was lowly expressed in gastric cancer tissues and cell lines. Overexpression of Ghrelin inhibited gastric cancer cell proliferation, migration, invasion, and promoted apoptosis by activating the AMPK pathway, while d-[lys3]-GHRP-6 (a GHSR agonist) treatment relieved the effect, promoting tumorigenesis. Ghrelin knockdown increased the glucose uptake and lactic acid release, suggesting that Ghrelin elicited an anti-Warburg effect via AMPK pathway to inhibit gastric tumorigenesis. Ghrelin inhibits cell proliferation, migration, and invasion by eliciting an anti-Warburg effect via AMPK signaling pathway in gastric cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article.

References

  • Bai RX et al (2016) Ghrelin attenuates the growth of HO-8910 ovarian cancer cells through the ERK pathway. Braz J Med Biol Res 49(3):e5043

    Article  PubMed Central  CAS  Google Scholar 

  • Baniak N et al (2016) Gastric biomarkers: a global review. World J Surg Oncol 14(1):212

    Article  PubMed  PubMed Central  Google Scholar 

  • Bayliss JA et al (2016) Ghrelin-AMPK signaling mediates the neuroprotective effects of calorie restriction in Parkinson’s disease. J Neurosci 36(10):3049–3063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    PubMed  Google Scholar 

  • Carling D (2017) AMPK signalling in health and disease. Curr Opin Cell Biol 45:31–37

    Article  CAS  PubMed  Google Scholar 

  • Chang HR et al (2016) HNF4alpha is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer. Gut 65(1):19–32

    Article  CAS  PubMed  Google Scholar 

  • Charalampakis N et al (2018) Medical management of gastric cancer: a 2017 update. Cancer Med 7(1):123–133

    Article  PubMed  Google Scholar 

  • Chen JH et al (2011) Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-kappaB signaling pathway in glioma cells. J Cell Biochem 112(10):2931–2941

    Article  CAS  PubMed  Google Scholar 

  • Chen X et al (2013) Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells. Metabolism 62(5):743–752

    Article  CAS  PubMed  Google Scholar 

  • Choi YY, Noh SH, An JY (2017) A randomized controlled trial of Roux-en-Y gastrojejunostomy vs. gastroduodenostomy with respect to the improvement of type 2 diabetes mellitus after distal gastrectomy in gastric cancer patients. PLoS One 12(12):e0188904

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chopin L et al (2011) Ghrelin and cancer. Mol Cell Endocrinol 340(1):65–69

    Article  CAS  PubMed  Google Scholar 

  • Faubert B et al (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124

    Article  CAS  PubMed  Google Scholar 

  • Gao M, Dang F, Deng C (2019) beta-Cryptoxanthin induced anti-proliferation and apoptosis by G0/G1 arrest and AMPK signal inactivation in gastric cancer. Eur J Pharmacol 859:172528

    Article  CAS  PubMed  Google Scholar 

  • Gray SM, Page LC, Tong J (2019) Ghrelin regulation of glucose metabolism. J Neuroendocrinol 31(7):e12705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hardie DG, Alessi DR (2013) LKB1 and AMPK and the cancer-metabolism link—ten years after. BMC Biol 11:36

    Article  PubMed  PubMed Central  Google Scholar 

  • Hart PC et al (2015) MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat Commun 6:6053

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Yang XJ, Gao R (2016a) Research advances in the mechanisms of gastric cancer multidrug resistance. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 38(6):739–745

    PubMed  Google Scholar 

  • Huang D et al (2016b) Negative regulation of Bmi-1 by AMPK and implication in cancer progression. Oncotarget 7(5):6188–6200

    Article  PubMed  Google Scholar 

  • Kraus D et al (2016) Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression. Cell Mol Life Sci 73(6):1287–1299

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Zhang H (2016) Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci 73(2):377–392

    Article  CAS  PubMed  Google Scholar 

  • Li W et al (2015) Targeting AMPK for cancer prevention and treatment. Oncotarget 6(10):7365–7378

    Article  PubMed  PubMed Central  Google Scholar 

  • Li W et al (2018) CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1alpha axis to inhibit gastric tumorigenesis. Oncogene 37(50):6383–6398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lien GS et al (2016) Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways. Eur J Pharmacol 776:124–131

    Article  CAS  PubMed  Google Scholar 

  • Lin SC, Hardie DG (2018) AMPK: sensing glucose as well as cellular energy status. Cell Metab 27(2):299–313

    Article  CAS  PubMed  Google Scholar 

  • Lin TC et al (2015) Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. J Pathol 237(1):50–61

    Article  CAS  PubMed  Google Scholar 

  • Lin TC et al (2019) Ghrelin upregulates oncogenic aurora A to promote renal cell carcinoma invasion. Cancers (Basel) 11(3):303

    Article  CAS  Google Scholar 

  • Liu J et al (2016) A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway. J Hematol Oncol 9(1):76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ngo DC et al (2015) Introduction to the molecular basis of cancer metabolism and the Warburg effect. Mol Biol Rep 42(4):819–823

    Article  CAS  PubMed  Google Scholar 

  • Pereira J, da Silva FC, de Moraes-Vieira PMM (2017) The impact of ghrelin in metabolic diseases: an immune perspective. J Diabetes Res 2017:4527980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Poher AL, Tschop MH, Muller TD (2018) Ghrelin regulation of glucose metabolism. Peptides 100:236–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pradhan G, Samson SL, Sun Y (2013) Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care 16(6):619–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pritchett NR et al (2020) Serum ghrelin and esophageal and gastric cancer in two cohorts in China. Int J Cancer 146(10):2728–2735

    Article  CAS  PubMed  Google Scholar 

  • Schwartz L, Supuran CT, Alfarouk KO (2017) The Warburg effect and the hallmarks of cancer. Anticancer Agents Med Chem 17(2):164–170

    Article  CAS  PubMed  Google Scholar 

  • Sever S, White DL, Garcia JM (2016) Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review. Endocr Relat Cancer 23(9):R393–R409

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen M et al (2019a) The long-term population impact of endoscopic screening programmes on disease burdens of gastric cancer in China: a mathematical modelling study. J Theor Biol 484:109996

    Article  PubMed  Google Scholar 

  • Shen Y et al (2019b) ARHGAP4 mediates the Warburg effect in pancreatic cancer through the mTOR and HIF-1alpha signaling pathways. Onco Targets Ther 12:5003–5012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soleyman-Jahi S et al (2017) Prognostic significance of preoperative and postoperative plasma levels of ghrelin in gastric cancer: 3-year survival study. Clin Transl Gastroenterol 8(1):e209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song Z et al (2017) Progress in the treatment of advanced gastric cancer. Tumour Biol 39(7):1010428317714626

    PubMed  Google Scholar 

  • Takaya K et al (2000) Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 85(12):4908–4911

    Article  CAS  PubMed  Google Scholar 

  • Tennakoon JB et al (2014) Androgens regulate prostate cancer cell growth via an AMPK-PGC-1alpha-mediated metabolic switch. Oncogene 33(45):5251–5261

    Article  CAS  PubMed  Google Scholar 

  • Tian C et al (2013) Ghrelin induces gastric cancer cell proliferation, migration, and invasion through GHS-R/NF-kappaB signaling pathway. Mol Cell Biochem 382(1–2):163–172

    Article  CAS  PubMed  Google Scholar 

  • Wu Y et al (2016) AMPK activator AICAR promotes 5-FU-induced apoptosis in gastric cancer cells. Mol Cell Biochem 411(1–2):299–305

    Article  CAS  PubMed  Google Scholar 

  • Xiao S, Zhou L (2017) Gastric cancer: metabolic and metabolomics perspectives (Review). Int J Oncol 51(1):5–17

    Article  CAS  PubMed  Google Scholar 

  • Xu Y et al (2013) Ghrelin inhibits ovarian epithelial carcinoma cell proliferation in vitro. Oncol Rep 30(5):2063–2070

    Article  CAS  PubMed  Google Scholar 

  • Xu DH et al (2018) Transmembrane protein GRINA modulates aerobic glycolysis and promotes tumor progression in gastric cancer. J Exp Clin Cancer Res 37(1):308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Youn GJ, Chung WC (2017) Micrometastasis in gastric cancer. Korean J Gastroenterol 69(5):270–277

    Article  PubMed  Google Scholar 

  • Zub-Pokrowiecka A et al (2011) Ghrelin and gastrin in advanced gastric cancer before and after gastrectomy. World J Gastroenterol 17(4):449–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The present study was supported by Fundamental Research Funds for the Central Universities of Southwest University (Grant No. XDJK2018C083); Associative Medical Research Project of Health and Science in Chongqing in 2019 (Grant No. 2019ZDXM032).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Southwest University Hospital, Chongqing, 400715, People’s Republic of China

    Xiao-Lin Hu & Juan Wu

  2. Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China

    Yong-Jun Zhu

  3. College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, People’s Republic of China

    Chang-Hua Hu & Xiao-Yan He

  4. Department of Pharmacy, Southwest University Hospital, Chongqing, 400715, People’s Republic of China

    Li You

  5. Health Management Center, Southwest University Hospital, No. 2, Tiansheng Road, Beibei District, Chongqing, 400715, People’s Republic of China

    Wen-Jie Huang & Zong-Hui Wu

Authors
  1. Xiao-Lin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-Jun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang-Hua Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li You
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao-Yan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-Jie Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zong-Hui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

(1) Conception and design: ZHW, XLH, and JW. (2) Administrative support: ZHW, XLH, and CHH. (3) Provision of study materials or patients: CHH and JW. (4) Collection and assembly of data: YJZ, XYH, and LY. (5) Data analysis and interpretation: LY and WJH. (6) Manuscript writing: All authors. (7) Final approval of manuscript: All authors.

Corresponding author

Correspondence to Zong-Hui Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The present study has obtained the patient’s informed consent and has been approved by Ethics Committee of Southwest University Hospital.

Consent for Publication

The informed consent was obtained from study participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, XL., Zhu, YJ., Hu, CH. et al. Ghrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway. Biochem Genet 59, 652–667 (2021). https://doi.org/10.1007/s10528-020-10022-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-020-10022-x

Keywords

Search

Navigation