3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3.
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed and closely linked with proliferation, survival, metastasis and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. We found that 3-formylchromone (3FC) inhibited both constitutive and inducible STAT3 activation in multiple myeloma (MM) cells. Besides the inhibition of STAT3 phosphorylation, 3FC also abrogated constitutive activity and nuclear translocation of STAT3. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and Src. Furthermore, 3FC induced the expression of the protein inhibitors of activated STAT3 (PIAS3), and gene silencing of the PIAS3 by small interfering RNA abolished the ability of 3FC to inhibit STAT3 activation, suggesting a critical role for PIAS3 in the action of 3FC. 3FC also downregulated the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xl, Mcl-1, Survivin, inhibitor of apoptosis protein-1 (IAP-1), Cyclin D1, cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9) in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced poly ADP ribose polymerase (PARP) cleavage. Overall, these results suggest that 3FC is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers.
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Jeong-Hyeon
JH
Ko
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Seung
S
Ho Baek
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Dongwoo
D
Nam
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Won-Seok
WS
Chung
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Seok-Geun
SG
Lee
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Junhee
J
Lee
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Woong
W
Mo Yang
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Jae-Young
JY
Um
a College of Korean Medicine , Kyung Hee University , Dongdaemun-Gu , Seoul , Korea.
Kwang
K
Seok Ahn
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology*; D006801:Humans; D018832:Molecular Chaperones / Q000276:immunology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000276:immunology*; D050828:Protein Inhibitors of Activated STAT / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
D002867:Chromones; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
3-Formylchromone; PIAS3; STAT3; apoptosis; multiple myeloma