Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells.

International Journal of Cancer. Journal International Du Cancer
Manoj K PandeyBharat B Aggarwal

Abstract

STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10 to 55%) and bortezomib (from 5 to 70%) in M...Continue Reading

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Citations

Aug 2, 2013·Nature Reviews. Drug Discovery·Gabriella MiklossyJames Turkson
May 3, 2011·European Journal of Medicinal Chemistry·Kuen-Feng ChenChung-Wai Shiau
Sep 22, 2011·International Journal of Cancer. Journal International Du Cancer·Ajaikumar B KunnumakkaraBharat B Aggarwal
Jun 3, 2015·Medicinal Research Reviews·Dong-Mei ZhangWen-Cai Ye
Jan 7, 2014·Biochimica Et Biophysica Acta·Kodappully Sivaraman SiveenAnupam Bishayee
Mar 23, 2011·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Sora ParkSung-Hoon Kim
Dec 3, 2014·Ageing Research Reviews·Orli SagiVadim E Fraifeld
Nov 5, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Runlan LuoZeyao Tang
Jun 9, 2017·International Journal of Molecular Sciences·Tzu-Ting HuangKuen-Feng Chen
Aug 17, 2017·Anais Da Academia Brasileira De Ciências·Mauricio M VictorAna J Araújo
Oct 26, 2016·Molecular Medicine Reports·Xia ZhangYan Chen
Jun 3, 2021·International Journal of Molecular Sciences·Dorina CoricovacMirela Danina Muntean
Jun 3, 2021·Cancers·Karin Jöhrer, Serhat Sezai Ҫiҫek

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