title: IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin.
abstract: Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP) dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Jun-Ai
authors.initials: JA
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Laboratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Wu
authors.affiliation: Department of Pathology, Dongguan 5th Hospital, Dongguan 523905, China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Liang
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Yuan-Bin
authors.initials: YB
authors.lastname: Lu
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Gao
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: You-Chao
authors.initials: YC
authors.lastname: Dai
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Shi-Yan
authors.initials: SY
authors.lastname: Yu
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Fu
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.affiliation: Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, No. 1 Xincheng Road, Dongguan 523808, China; Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, No. 1 Xincheng Road, Dongguan 523808, China.
authors.forename: Jun-Fa
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jixin
authors.identifier: 0000-0003-2196-678X
authors.initials: J
authors.lastname: Zhong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D016190:Carboplatin