^{Cancer Biology & Anti-Cancer Therapies and Drug Development & Delivery}

Biography

Biography: Andrei L. Gartel

Abstract

FOXM1 is an oncogenic transcription factor that is overexpressed in the majority of human cancers and it is a potential target for anticancer drugs. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Moreover, we found that HSP90 inhibitor PF-4942847 that does not act as proteasome inhibitor also suppresses FOXM1. Chaperone HSP70 is induced after treatment with both proteasome/HSP90 inhibitors and after heat-shock stress and we identified this chaperone as a novel negative regulator of FOXM1 after proteotoxic stress. We showed that FOXM1 and HSP70 interact in cancer cells following proteotoxic stress and FOXM1/HSP70 interaction led to inhibition of FOXM1. Honokiol is a natural product and an emerging drug for a wide variety of malignancies, including hematopoietic malignancies, sarcomas, and common epithelial tumors. Here we found that honokiol inhibits FOXM1-mediated transcription and FOXM1 protein expression. More importantly, we found that honokiol’s inhibitory effect on FOXM1 is a result of direct binding of honokiol to FOXM1. This binding is specific to honokiol, a dimerized allylphenol, and was not observed in compounds that either were monomeric allylphenol or un-substituted dihydroxy phenols. This indicates that both substitution and dimerization of allylphenol are required for physical interaction with FOXM1. We have previously shown that FOXM1 interacts with nucleophosmin (NPM) in cancer cells and NPM determines the cellular localization of FOXM1. Mutations in NPM1 result in cytoplasmic re-localization of NPM (NPM1^mut) and favorable outcome for the patients. We found the evidence that improved outcomes in the subset of NPM1^mut AML may be partially explained by the cytoplasmic re-localization and consequent functional inactivation of FOXM1. First, we confirmed the co-localization of FOXM1 and NPM^mut in the cytoplasm of AML patients bone marrow biopsies and determined a strong cytoplasmic expression of FOXM1 only in NPM1^mut AML cells. We also showed an important role of FOXM1 in chemo-resistance in leukemia cell lines with nuclear, but not cytoplasmic FOXM1. These data imply that suppressing of FOXM1 in AML could increase sensitivity to standard chemotherapy, while overexpression of FOXM1 would increase chemo-resistance of AML cells. We developed novel drugs that inhibit the interaction between NPM and FOXM1 and FOXM1 expression in human cancer cells and potentially may be used against human cancer.