Oligomannurarate sulfate sensitizes cancer cells to doxorubicin by inhibiting atypical activation of NF-[kappa]B via targeting of Mre11

Aberrant regulation of nuclear factor kappa B (NF-[kappa]B) 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-[kappa]B 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-[kappa]B 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-[alpha]-mediated NF-[kappa]B activation. This selective inactivation of the specific NF-[kappa]B 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-[kappa]B inhibitors provides a platform for the further development of effective anticancer agents. [PUBLICATION ABSTRACT]