title: AKT activation controls cell survival in response to HDAC6 inhibition.
abstract: HDAC6 is emerging as an important therapeutic target for cancer. We investigated mechanisms responsible for survival of tumor cells treated with a HDAC6 inhibitor. Expression of the 20 000 genes examined did not change following HDAC6 treatment in vivo. We found that HDAC6 inhibition led to an increase of AKT activation (P-AKT) in vitro, and genetic knockdown of HDAC6 phenocopied drug-induced AKT activation. The activation of AKT was not observed in PTEN null cells; otherwise, PTEN/PIK3CA expression per se did not predict HDAC6 inhibitor sensitivity. Interestingly, HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380), which likely led to the increased P-AKT in cells that express PTEN. Synergy was observed with phosphatidylinositol 3'-kinases (PI3K) inhibitor treatment in vitro, accompanied by increased caspase 3/7 activity. Furthermore, combination of HDAC6 inhibitor with a PI3K inhibitor caused substantial tumor growth inhibition in vivo compared with either treatment alone, also detectable by Ki-67 immunostaining and (18)F-FLT positron emission tomography (PET). In aggregate AKT activation appears to be a key survival mechanism for HDAC6 inhibitor treatment. Our findings indicate that dual inhibition of HDAC6 and P-AKT may be necessary to substantially inhibit growth of solid tumors.
authors.affiliation: Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kaliszczak
authors.affiliation: Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Trousil
authors.affiliation: Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ali
authors.affiliation: Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: E O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053148:Caspase 3; D053179:Caspase 7; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases