title: MPT0B098, a Microtubule Inhibitor, Suppresses JAK2/STAT3 Signaling Pathway through Modulation of SOCS3 Stability in Oral Squamous Cell Carcinoma.
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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.|Department of Life Sciences, National Central University, Taoyuan, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Peng
authors.affiliation: Department of Medical Research, Show Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Guan-Hsun
authors.initials: GH
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medical, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Central University, Taoyuan, Taiwan.
authors.forename: Shiow-Lian Catherine
authors.initials: SL
authors.lastname: Jin
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D025461:Feedback, Physiological / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000473:pathology*; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D020836:Protein Structure, Quaternary; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*; D053634:TYK2 Kinase / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D007211:Indoles; C000621717:MPT0B098; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D000071223:Suppressor of Cytokine Signaling 3 Protein; D014404:Tubulin; D050257:Tubulin Modulators; C057812:indoline; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D002945:Cisplatin; D005472:Fluorouracil