The AMPK-activator AICAR in Thyroid Cancer: Effects on CXCL8 Secretion and on CXCL8-induced Neoplastic Cell Migration

Overview

Journal J Endocrinol Invest

Publisher Springer

Specialty Endocrinology

Date 2018 Mar 17

PMID 29546654

Citations 16

Authors

O Awwad

F Coperchini

P Pignatti

M Denegri

S Massara

L Croce

C A Di Buduo

V Abbonante

A Balduini

L Chiovato

M Rotondi

Affiliations

Soon will be listed here.

Abstract

Purpose: The AMPK-activator AICAR recently raised great interest for its anti-cancer properties. With specific regard to thyroid cancer, AICAR reduces cancer cell growth, invasion and metastasis. CXCL8, a chemokine with several recognized tumorigenic effects, is abundantly secreted in thyroid cancer microenvironment. The aim of this study was to investigate if AICAR could inhibit the basal and the TNFα-induced CXCL8 secretion in normal human thyroid cells (NHT) and in thyroid cancer cell lines TPC-1 and BCPAP (RET/PTC and BRAFV600e mutated, respectively).

Methods: The effect of AICAR on basal and CXCL8-induced cell migration was assessed. Cells were incubated with AICAR (0.05, 0.5, 1, 2 mM) alone or in combination with TNF-α (10 ng/ml) for 24 h. CXCL8 concentrations were measured in cell supernatants. Transwell migration assays were performed in NHT, TPC-1 and BCPAP, basally and after treatment with AICAR (2 mM) and rh-CXCL8 (50 ng/ml) alone or in combination.

Results: AICAR dose dependently inhibited the basal secretion of CXCL8 in TPC-1 (F = 4.26; p < 0.007) and BCPAP (F = 6.75; p < 0.0001) but not in NHT. TNFα-induced CXCL8 secretion was dose dependently reduced by AICAR in NHT (F = 9.99; p < 0.0001), TPC-1 (F = 9.25; p < 0.0001) and BCPAP (F = 6.82; p < 0.0001). AICAR significantly reduced the basal migration of TPC-1 and BCPAP but not of NHT.

Conclusions: CXCL8-induced cell migration was inhibited in NHT, TPC-1 and BCPAP. This is the first demonstration of the inhibition of CXCL8 secretion exerted by AICAR in TPC-1 and BCPAP indicating that the anti-cancer properties of AICAR are, at least in part, mediated by its ability to reduce the pro-tumorigenic effects of CXCL8.

Citing Articles

Vitamin C in the Management of Thyroid Cancer: A Highway to New Treatment?.

Gorini F, Tonacci A Antioxidants (Basel). 2024; 13(10).

PMID: 39456495 PMC: 11505632. DOI: 10.3390/antiox13101242.

Li M, Fu X, Zhou T, Han H BMC Med Genomics. 2024; 17(1):199.

PMID: 39113023 PMC: 11304613. DOI: 10.1186/s12920-024-01975-8.

Selective anti-CXCR2 receptor blockade by AZD5069 inhibits CXCL8-mediated pro-tumorigenic activity in human thyroid cancer cells in vitro.

Coperchini F, Greco A, Petrosino E, Croce L, Teliti M, Marchesi N J Endocrinol Invest. 2024; 48(1):53-65.

PMID: 38900374 PMC: 11729135. DOI: 10.1007/s40618-024-02410-6.

AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer.

Pokhrel R, Acharya S, Mishra S, Gu Y, Manzoor U, Kim J Biomol Ther (Seoul). 2024; 32(2):171-182.

PMID: 38346909 PMC: 10902700. DOI: 10.4062/biomolther.2023.222.

Long non-coding RNA ACTA2-AS1 suppresses metastasis of papillary thyroid cancer via regulation of miR-4428/KLF9 axis.

Wu S, Zhu J, Jiang T, Cui T, Zuo Q, Zheng G Clin Epigenetics. 2024; 16(1):10.

PMID: 38195623 PMC: 10775490. DOI: 10.1186/s13148-023-01622-6.

References

Cheng X, Li Y, Huang C, Li J, Yao H . AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema. Oncotarget. 2017; 8(14):22513-22523. PMC: 5410241. DOI: 10.18632/oncotarget.15116. View

Kim H, Kim M, Kim E, Yang Y, Lee M, Lim J . Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression. Biochem Pharmacol. 2011; 83(3):385-94. DOI: 10.1016/j.bcp.2011.11.008. View

Fernando R, Castillo M, Litzinger M, Hamilton D, Palena C . IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 2011; 71(15):5296-306. PMC: 3148346. DOI: 10.1158/0008-5472.CAN-11-0156. View

Shen C, Ka S, Kim S, Kim J, Park B, Park J . Metformin and AICAR regulate NANOG expression via the JNK pathway in HepG2 cells independently of AMPK. Tumour Biol. 2016; 37(8):11199-208. DOI: 10.1007/s13277-016-5007-0. View

Andrade B, Cazarin J, Zancan P, Carvalho D . AMP-activated protein kinase upregulates glucose uptake in thyroid PCCL3 cells independent of thyrotropin. Thyroid. 2012; 22(10):1063-8. DOI: 10.1089/thy.2012.0041. View

Owen M, Doran E, Halestrap A . Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348 Pt 3:607-14. PMC: 1221104. View

Kuo C, Ho F, Chang M, Prakash E, Lin W . Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. J Cell Biochem. 2007; 103(3):931-40. DOI: 10.1002/jcb.21466. View

Coperchini F, Pignatti P, Leporati P, Carbone A, Croce L, Magri F . Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion. Endocrine. 2015; 54(1):123-128. DOI: 10.1007/s12020-015-0764-x. View

Rattan R, Giri S, Singh A, Singh I . 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem. 2005; 280(47):39582-93. DOI: 10.1074/jbc.M507443200. View

10.

Qin S, Ni M, De Vries G . Implication of S-adenosylhomocysteine hydrolase in inhibition of TNF-alpha- and IL-1beta-induced expression of inflammatory mediators by AICAR in RPE cells. Invest Ophthalmol Vis Sci. 2008; 49(3):1274-81. DOI: 10.1167/iovs.07-1109. View

11.

Visciano C, Liotti F, Prevete N, Cali G, Franco R, Collina F . Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway. Oncogene. 2015; 34(40):5175-86. DOI: 10.1038/onc.2014.441. View

12.

Morishita M, Kawamoto T, Hara H, Onishi Y, Ueha T, Minoda M . AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway. Int J Oncol. 2016; 50(1):23-30. PMC: 5182012. DOI: 10.3892/ijo.2016.3775. View

13.

Bridges H, Sirvio V, Agip A, Hirst J . Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. BMC Biol. 2016; 14:65. PMC: 4977651. DOI: 10.1186/s12915-016-0287-9. View

14.

Saeedi R, Parsons H, Wambolt R, Paulson K, Sharma V, Dyck J . Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms. Am J Physiol Heart Circ Physiol. 2008; 294(6):H2497-506. DOI: 10.1152/ajpheart.00873.2007. View

15.

Nie J, Liu A, Tan Q, Zhao K, Hu K, Li Y . AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells. Biochem Biophys Res Commun. 2016; 482(2):246-252. DOI: 10.1016/j.bbrc.2016.11.050. View

16.

Rotondi M, Coperchini F, Pignatti P, Magri F, Chiovato L . Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: an additional indirect anti-tumor effect of the drug. J Clin Endocrinol Metab. 2015; 100(3):E427-32. DOI: 10.1210/jc.2014-3045. View

17.

Sui X, Xu Y, Yang J, Fang Y, Lou H, Han W . Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One. 2014; 9(5):e97781. PMC: 4029793. DOI: 10.1371/journal.pone.0097781. View

18.

Andrade B, Pires de Carvalho D . Perspectives of the AMP-activated kinase (AMPK) signalling pathway in thyroid cancer. Biosci Rep. 2016; 34(2). PMC: 3986867. DOI: 10.1042/BSR20130134. View

19.

Rotondi M, Coperchini F, Awwad O, Pignatti P, Di Buduo C, Abbonante V . Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation. Mediators Inflamm. 2016; 2016:8512417. PMC: 4983361. DOI: 10.1155/2016/8512417. View

20.

Fang W, Ye L, Shen L, Cai J, Huang F, Wei Q . Tumor-associated macrophages promote the metastatic potential of thyroid papillary cancer by releasing CXCL8. Carcinogenesis. 2014; 35(8):1780-7. DOI: 10.1093/carcin/bgu060. View