Abstract
Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC). Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.
Highlights
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is frequently dysregulated in various human cancer cells [1] and plays a critical role in oncogenesis including proliferation, apoptosis, drug resistance, migration, invasion and PLOS ONE | DOI:10.1371/journal.pone.0158440 July 1, 2016MPT0B098 Modulates SOCS3 Stability angiogenesis [2]
We found that the total protein and phosphorylation levels of JAK2, TYK2 and STAT3 were significantly decreased in the oral squamous cell carcinoma (OSCC) cells transfected with a SOCS3 cDNA construct (Fig 4B)
Overexpression of SOCS3 protein in OEC-M1 and HSC-3 cells markedly increased the MPT0B098-induced apoptosis (Fig 4C).knockdown of SOCS3 protein in DOK and YD-15 cells significantly attenuated the MPT0B098-induced apoptosis (Fig 4D). These results suggest that the induction of cancer cell apoptosis by MPT0B098 may be mediated by a negative modulation of SOCS3 on JAK2/STAT3 signaling pathway
Summary
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is frequently dysregulated in various human cancer cells [1] and plays a critical role in oncogenesis including proliferation, apoptosis, drug resistance, migration, invasion and PLOS ONE | DOI:10.1371/journal.pone.0158440 July 1, 2016MPT0B098 Modulates SOCS3 Stability angiogenesis [2]. There are two classical negative feedback regulators for the JAK/STAT signaling pathway, the protein inhibitors of activated STATs (PIAS) and the suppressors of cytokine signaling (SOCS), through which the STAT pathway is silenced by masking STAT binding sites on the receptors, by binding to JAKs to inhibit their kinase activity, or by targeting proteins for proteasomal degradation through ubiquitination [8, 9]. Among these negative regulators, SOCS3 is known to attenuate interleukin-6 (IL-6) induced STAT3 activation [10, 11]. SOCS3 is regarded as a useful diagnostic molecule and a potential therapeutic target for HNSCC
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