Activation of signal transducers and activators of transcription-3 (STAT-3) has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, including human multiple myeloma (MM).
Our major findings were: (1) one or more of the three genes was frequently methylated in L/L and MM cell lines and there was good concordance (90-100%) between methylation and loss of gene expression; (2) treatment of L/L cell lines with a demethylating agent resulted in re-expression of SHP1 protein and downregulation of phosphorylated STAT3 in L/L cell lines; (3) all 55 control specimens and the lymphoblastoid cultures were negative for methylation of the three genes; (4) non-Hodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (<30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (<20%), and occasional methylation of SOCS1 and SYK; and (6) comparable methylation frequencies for SOCS1 were observed in MM and MGUS, suggesting that SOCS1 methylation is an early event in MM pathogenesis.
This elucidation of the role of PIAS3 in the miR-21-STAT3 positive regulatory loop not only may shed light on the molecular basis of the biological effects of miR-21 observed in MM cells but also has direct implications for the development of novel anti-MM therapeutic strategies.
In this study, we evaluated the effect of the ethanol extract of Patrinia scabiosaefolia (EEPS) on proliferation and apoptosis in human multiple myeloma U266 cells that persistently express phosphorylated STAT3, and investigated the possible molecular mechanisms mediating its biological effects.
In previous studies we identified microRNA-21 as a STAT3 target gene with strong anti-apoptotic potential, suggesting that noncoding RNAs have an impact on the pathogenesis of human multiple myeloma.
GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in multiple myeloma (MM) tumor cells.
Our previous work demonstrated that the Janus kinase (JAK)-Stat3 pathway regulates expression of Bcl-x(L) in the U266 human multiple myeloma cell line and prevents Fas-mediated apoptosis.
Overall, our results indicate that fresh cells from MM patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells.
Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells.
Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity.
In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis.
Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers).
Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy.
We found that ursolic acid, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in multiple myeloma cells.
Proliferation measured as extracellular signal-regulated kinase (ERK) and immunoglobulin G (Ig G) expression and apoptosis measured as fluorescence-activated cell sorting (FACS) with annexin V method, caspase-3, and stat-3 expression were assessed for cultured MM plasma cells, along with expression of sclerostin.
Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM.
We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266.
Adherence of MM cells to bone marrow stromal cells (BMSCs) induced increased Mcl-1 expression associated with signal transducer and activator of transcription 3 (STAT3) phosphorylation, which was inhibited in a time- and dose-dependent manner by seliciclib.
Interestingly, arctiin could not repress IL-6-induced STAT3 activation in serum-starved U266 cells and when arctiin was incubated with a complete culture medium in RPMI 8226 and MM.1S cells.
Activation of pro-inflammatory transcription factors NF-κB and signal transducer and activator of transcription 3 (STAT3) is one of the major contributors to both pathogenesis and chemoresistance in multiple myeloma (MM), which results in high mortality rate.