Nuclear receptors as negative modulators of STAT3 in multiple myeloma.
Multiple myeloma (MM) remains largely incurable despite conventional and high-dose therapies. Therefore, novel biologically based treatment approaches are urgently required. Particularly, STAT3 activated by IL-6 has a key role in preventing apoptosis and stimulating growth of multiple myeloma cells. Nuclear receptors, a distinct class of ligand-activated transcriptional factors, can interact and modify the function of transcriptional factors intrinsic to the cytokine signal transduction pathways. We have investigated regulation of two nuclear receptors, peroxisome proliferator-activated receptor gamma (PPARgamma) and estrogen receptor (ER), and their crosstalk with STAT3 in multiple myeloma. These results indicate that ligand-activated nuclear receptors can function as negative modulators of STAT3 through direct mechanisms, or in turn, by facilitating coregulators such as PIAS or SMRT. Therefore, different classes of nuclear receptors affect suppression of STAT3 functions through diverse mechanisms resulting in downregulating IL-6-mediated cell growth and gene expression. Given the importance of IL-6 in multiple myeloma, the estrogen receptor-STAT3 or PPARgamma-STAT3 interaction may have significant therapeutic implications in multiple myeloma.
Wang
Li Hua
LH
Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA. lhwang@ncifcrf.gov
Yang
Xiao Yi
XY
Zhang
Xiaohu
X
Farrar
William L
WL
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D009101:Multiple Myeloma / Q000235:genetics / Q000503:physiopathology*; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000502:physiology; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D015850:Interleukin-6; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D050828:Protein Inhibitors of Activated STAT; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors