Biography
Biography: Andrei L Gartel
Abstract
FOXM1 is an oncogenic transcription factor that is overexpressed in 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. Chaperone HSP70 is induced after treatment with proteasome inhibitors 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 that inhibits FOXM1-mediated transcription and FOXM1 protein expression. 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 allylphenols or un-substituted dihydroxy phenols. We have previously shown that FOXM1 interacts with nucleophosmin (NPM) in cancer cells and NPM determines cellular localization of FOXM1. Mutations in NPM1 result in cytoplasmic re-localization of NPM (NPM1mut) and favorable outcome for the AML patients. We found the evidence that improved outcomes in the subset of NPM1mut AML may be partially explained by the cytoplasmic re-localization and consequent functional inactivation of FOXM1. We also showed an important role of FOXM1 in chemo-resistance in AML 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.