Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Bharti, Alok C.; Donato, Nicholas J.; Aggarwal, Bharat B.

doi:10.4049/jimmunol.171.7.3863

Cited by 478 publications

(326 citation statements)

References 72 publications

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“…Besides its effect on STAT proteins in leukemia cells, curcumin was also reported to be a reversible inhibitor of constitutive STAT3, but not STAT5 phosphorylation, in human MM cells (Bharti et al 2003). This was correlated with the inhibition of STAT3 nuclear translocation in MM cells.…”

Section: Multiple Myelomamentioning

confidence: 94%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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Section: Multiple Myelomamentioning

confidence: 94%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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“…Recently, two studies revealed the expression of constitutively active NF-kB in freshly drawn bone marrow aspirates from 37 of 37 MM patients. 40,41 Both studies demonstrated the retention of the NF-kB consensus sequence in nuclear extracts as well as translocation of the p65 subunit to the nucleus in highly purified CD138 þ MM plasma cells. The underlying mechanisms for expression of constitutively activated NF-kB in MM cells are poorly understood.…”

Section: Non-hodgkin's Lymphomamentioning

confidence: 96%

“…42 As a possibility, NF-kB might upregulate the expression of interleukin-6 (IL-6), which in turn activates STAT3. 40,41 The expression of Bcl-X L , a prominent antiapoptotic Bcl-2 homolog, is induced by both STAT3 and NF-kB, and Bcl-X L overexpression has been demonstrated in MM cells at the protein level. 42 The expression of Bcl-X L is negatively correlated with chemotherapy responses in MM.…”

Section: Non-hodgkin's Lymphomamentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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“…In studies of the myeloid cell line ML-1a, Singh and Aggarwal reported that curcumin inhibited IkBa phosphorylation, degradation, and NF-kB translocation induced by a diverse range of stimuli including TNF, hydrogen peroxide, and phorbol esters [2]. Subsequent studies confirmed curcumininduced inhibition of NF-kB translocation in multiple cell types, including colon [3], gastric [4], pancreatic [5], and squamous epithelial tumor cell lines [6] as well as B-cell lymphoma and multiple myeloma cell lines [7,8]. Although the precise mechanism by which NF-kB translocation is inhibited remains unclear, Plummer et al demonstrated that curcumin reduced NF-kB translocation in HEK293 cells transfected with NIK, IKKa, or IKKb kinases [3].…”

Section: Introductionmentioning

confidence: 91%

Preclinical assessment of curcumin as a potential therapy for B‐CLL

et al. 2006

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Curcumin, the principle component of the spice turmeric, has been used as an anti-inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B-CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARg or NF-kB signaling in curcumin-induced apoptosis was examined by cotreatment with a PPARg antagonist or EMSA of nuclear NFkB complexes. We also examined whether a clinically achievable concentration of curcumin (1 mM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B-CLL cells from 14 patients, curcumin-induced apoptosis with a mean EC 50 of 5.5 mM. In contrast, the EC 50 for whole mononuclear cells from a healthy donor was 21.8 mM. In a 48 hr wash-out time course, curcumin-induced apoptosis was time-dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-kB levels and 1 mM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B-CLL. Am. J. Hematol. 82:23-30, 2007. V V C 2006 Wiley-Liss, Inc.

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Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Cited by 478 publications

References 72 publications

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

Targeting NF-κB in hematologic malignancies

Preclinical assessment of curcumin as a potential therapy for B‐CLL

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