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Crocin Suppresses Constitutively Active STAT3 Through Induction of Protein Tyrosine Phosphatase SHP-1
Buyun Kim1, Ki Yong Lee2, Byoungduck Park1
1College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Republic of Korea.
Abstract:
The aim of the present study is to investigate the effect of a natural compound crocin, one of the active components of saffron, on human multiple myeloma cells. Crocin effectively suppressed constitutive STAT3 activation, translocation of STAT3 to the nucleus, and its target gene expression. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases JAK1, JAK2, and c-Src. We found that crocin induced the expression of SHP-1, a tyrosine protein phosphatase, and pervanadate treatment reversed the crocin-induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Moreover, suppression of SHP-1 by its inhibitor overturned the effect of crocin on induction of SHP-1 and the inhibition of STAT3 activation. Finally, crocin downregulated the expression of STAT3-mediated gene products including anti-apoptotic (Bcl-2), pro-apoptotic (BAX), invasive (CXCR4), angiogenic (VEGF), and cell cycle regulator (cyclin D1), which are correlated with suppression of proliferation, the accumulation of cells in sub-G1 phase of cell cycle, and induction of apoptosis. Overall, our results suggested that crocin is a novel inhibitor of STAT3 activation pathway and thus may have potential in prevention and treatment of human multiple myeloma. J. Cell. Biochem. 118: 3290-3298, 2017. © 2017 Wiley Periodicals, Inc.
Insights
Crocin, a saffron compound, inhibits STAT3 activation in multiple myeloma cells by targeting key kinases and phosphatases. This natural compound shows potential for preventing and treating multiple myeloma.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Multiple myeloma is a hematological malignancy characterized by uncontrolled proliferation of plasma cells.
- Constitutive activation of the STAT3 signaling pathway is frequently observed in multiple myeloma and contributes to tumor growth and survival.
Purpose of the Study:
- To investigate the effect of crocin, a natural compound from saffron, on STAT3 activation in human multiple myeloma cells.
- To elucidate the molecular mechanisms underlying crocin's action on the STAT3 pathway.
Main Methods:
- Crocin treatment of human multiple myeloma cells.
- Western blot analysis to assess protein expression and activation (STAT3, JAK1, JAK2, c-Src, SHP-1).
- Quantitative real-time PCR to evaluate target gene expression.
- Flow cytometry to analyze cell cycle distribution and apoptosis.
Main Results:
- Crocin suppressed STAT3 activation, nuclear translocation, and target gene expression in multiple myeloma cells.
- Crocin's effect was mediated by inhibiting JAK1, JAK2, and c-Src kinases and inducing SHP-1 phosphatase.
- Crocin downregulated STAT3-regulated genes involved in apoptosis, invasion, angiogenesis, and cell cycle progression, leading to reduced proliferation and induced apoptosis.
Conclusions:
- Crocin acts as a novel inhibitor of the STAT3 activation pathway.
- Crocin demonstrates potential therapeutic value for the prevention and treatment of human multiple myeloma.
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