Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101083777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1582-4934 (Electronic) Linking ISSN: 15821838 NLM ISO Abbreviation: J Cell Mol Med Subsets: MEDLINE

Publication: Oxford, England : Wiley-Blackwell
Original Publication: Bucharest : "Carol Davila" University Press, 2000-

Mutation*; Curcumin/*pharmacology ; Janus Kinase 2/*antagonists & inhibitors ; Leukemia, Erythroblastic, Acute/*pathology ; Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors ; Myeloproliferative Disorders/*pathology ; STAT Transcription Factors/*antagonists & inhibitors; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; Apoptosis ; Biomarkers, Tumor ; Case-Control Studies ; Cell Movement ; Cell Proliferation ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism ; Leukemia, Erythroblastic, Acute/drug therapy ; Leukemia, Erythroblastic, Acute/metabolism ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/pathology ; Male ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Middle Aged ; Myeloproliferative Disorders/drug therapy ; Myeloproliferative Disorders/metabolism ; Phosphorylation ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Young Adult

Myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive and negative. The JAK2 V617F is the most common mutation in Philadelphia negative patients and results in a constitutive activation of the JAK/STAT pathway, conferring a proliferative advantage and apoptosis inhibition. Recent studies identified a functional crosstalk between the JAK/STAT and mTOR pathways. The identification of an effective therapy is often difficult, so the availability of new therapeutic approaches might be attractive. Previous studies showed that curcumin, the active principle of the Curcuma longa, can suppress JAK2/STAT pathways in different type of cancer and injuries. In this study, we investigated the anti-proliferative and pro-apoptotic effects of curcumin in JAK2 V617F-mutated cells. HEL cell line and cells from patients JAK2 V617F mutated have been incubated with increasing concentrations of curcumin for different time. Apoptosis and proliferation were evaluated. Subsequently, JAK2/STAT and AKT/mTOR pathways were investigated at both RNA and protein levels. We found that curcumin induces apoptosis and inhibition of proliferation in HEL cells. Furthermore, we showed that curcumin inhibits JAK2/STAT and mTORC1 pathways in JAK2 V617F-mutated cells. This inhibition suggests that curcumin could represent an alternative strategy to be explored for the treatment of patients with myeloproliferative neoplasms.
(© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Clin Cancer Res. 2013 Apr 15;19(8):1933-40. (PMID: 23406773)
Leukemia. 2014 Nov;28(11):2267-70. (PMID: 25027516)
Exp Hematol. 2015 Aug;43(8):599-608. (PMID: 26209551)
Oncotarget. 2017 May 22;8(57):96710-96724. (PMID: 29228564)
Blood. 2017 Feb 16;129(7):832-837. (PMID: 28031182)
J Altern Complement Med. 2003 Feb;9(1):161-8. (PMID: 12676044)
Mol Cell. 2011 Dec 23;44(6):864-77. (PMID: 22195962)
Oncotarget. 2015 Nov 24;6(37):40141-57. (PMID: 26472029)
Eur J Cancer. 2005 Sep;41(13):1955-68. (PMID: 16081279)
Curr Cancer Drug Targets. 2005 Mar;5(2):117-29. (PMID: 15810876)
Blood. 2008 Sep 15;112(6):2190-8. (PMID: 18779404)
J Transl Med. 2004 Mar 29;2(1):8. (PMID: 15050027)
Mol Med Rep. 2016 Jan;13(1):592-604. (PMID: 26648561)
Oncotarget. 2014 Sep 30;5(18):8503-14. (PMID: 25238262)
J Immunol. 2003 Dec 1;171(11):6072-9. (PMID: 14634121)
Blood. 2012 Mar 22;119(12):2721-30. (PMID: 22279053)
PLoS One. 2013;8(1):e54826. (PMID: 23382981)
J Cell Mol Med. 2019 Jun;23(6):4349-4357. (PMID: 31033209)
Anticancer Res. 2003 Jan-Feb;23(1A):363-98. (PMID: 12680238)
Br J Haematol. 2012 Oct;159(2):237-40. (PMID: 22924455)
Genes Cancer. 2010 Oct;1(10):979-93. (PMID: 21442038)
Carcinogenesis. 2013 Jul;34(7):1442-9. (PMID: 23430957)
Biochim Biophys Acta. 2010 Sep;1803(9):991-1002. (PMID: 20399811)
J Biol Chem. 2005 Sep 16;280(37):32081-9. (PMID: 16027121)
Cancer Res. 2009 Feb 1;69(3):1000-8. (PMID: 19176385)
Oncotarget. 2018 Jun 1;9(42):26834-26851. (PMID: 29928488)
Expert Opin Drug Saf. 2013 Mar;12(2):177-86. (PMID: 23252795)
Exp Ther Med. 2017 Aug;14(2):1669-1674. (PMID: 28810635)
Invest New Drugs. 2010 Dec;28 Suppl 1:S50-7. (PMID: 21127942)
Oncol Rep. 2015 Dec;34(6):3311-7. (PMID: 26397387)
Cell. 2009 May 29;137(5):873-86. (PMID: 19446321)

Keywords: JAK/STAT; JAK2 V617F; Myeloproliferative neoplasms; curcumin; mTORC1

0 (Antineoplastic Agents)
0 (Biomarkers, Tumor)
0 (STAT Transcription Factors)
EC 2.7.10.2 (JAK2 protein, human)
EC 2.7.10.2 (Janus Kinase 2)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
IT942ZTH98 (Curcumin)

Date Created: 20190430 Date Completed: 20200729 Latest Revision: 20210109

20221213

PMC6533565

10.1111/jcmm.14326

31033209