Oligomannurarate sulfate sensitizes cancer cells to doxorubicin by inhibiting atypical activation of NF-κB via targeting of Mre11

Authors

  • Jing Zhang,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Xianliang Xin,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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    • X.X and Q.C. contributed equally to this work

  • Qin Chen,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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    • X.X and Q.C. contributed equally to this work

  • Zuoquan Xie,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Min Gui,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Yi Chen,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Liping Lin,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Jianming Feng,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Qiuning Li,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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  • Jian Ding,

    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
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    • Fax: 86-21-50806722

  • Meiyu Geng

    Corresponding author
    1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peoples Republic of China
    • Shanghai Institute of Materia Medica, 555 Zuchongzhi Road, Shanghai 201203, Peoples Republic of China, Tel.: 86-21-50806072
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    • Fax: 86-21-50806072


Abstract

Aberrant regulation of nuclear factor kappa B (NF-κB) transcription factor is involved in cancer development, progression and resistance to chemotherapy. JG3, a marine-derived oligomannurarate sulfate, was reported as a heparanase and NF-κB inhibitor to significantly block tumor growth and metastasis in various animal models. However, the detailed functional mechanism remains unclear. Here, we report that JG3 inhibits NF-κB activation by specifically antagonizing the doxorubicin-triggered Ataxia-telangiectasia-mutated kinase (ATM) and the sequential MEK/ERK/p90Rsk/IKK signaling pathway but does not interfere with TNF-α-mediated NF-κB activation. This selective inactivation of the specific NF-κB cascade is attributed to the binding capacity of JG3 for Mre11, a major sensor of DNA double-strand breaks (DSB). Based on this selective mechanism, JG3 showed synergistic effect with doxorubicin in a panel of tumor cells and did not affect immune system function as shown in the in vivo delayed-type hypersensitivity (DTH) and hemolysis assays. All these highlight the clinical potential of JG3 as a favorable sensitizer in cancer therapy. In addition, identification of Mre11 as a potential target in the development of NF-κB inhibitors provides a platform for the further development of effective anticancer agents.

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