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

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 MM cells. Overall, our results suggest that betulinic acid downregulates STAT3 activation through upregulation of SHP-1, and this may have potential in sensitization of STAT3 overexpressing tumors to chemotherapeutic agents.

Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer

“…More recently, increasing attention has been devoted to the aberrant activation of STAT3 for its critical role in tumor progression (33)(34)(35). However, therapeutic agents targeting STAT3 signaling pathway are still limited.…”

Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma

“…[21][22][23] We next examined whether PF4 could inhibit IL-6-induced STAT3 activation. NCI-H929 cells were stimulated with 10 ng/mL IL-6 for different periods.…”

Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro

“…Betulinic acid (BA), a natural pentacyclic triterpene isolated from birch, exhibits a variety of biological activities, including anti-HIV, anti-HBV, anti-malarial [8][9][10] and potent anti-tumor properties in melanoma [11] , leukemia [12] , colon [13] , lung [14] , gliomas [15] , prostate carcinoma [16] , gastric adenocarcinoma [17] and multiple myeloma [18,19] . Various mechanisms have been reported for the extensive anticancer activity of BA, including directly triggering mitochondrial membrane permeabilization [20] , regulating Bcl-2 family proteins [21] , downregulating Hiwi expression [17] and suppressing the activation of the STAT3 pathway through the induction of the protein tyrosine phosphatase SHP-1 [19] .…”

“…Various mechanisms have been reported for the extensive anticancer activity of BA, including directly triggering mitochondrial membrane permeabilization [20] , regulating Bcl-2 family proteins [21] , downregulating Hiwi expression [17] and suppressing the activation of the STAT3 pathway through the induction of the protein tyrosine phosphatase SHP-1 [19] . However, there are no reports as to whether BA has any effects on cancer cell autophagy.…”