title: Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis.
abstract: Both Akt 2 and acid ceramidase (ASAH1) are found aberrantly overexpressed in cancer cells, but whether these two enzymes cooperate to induce malignant transformation is not known. We found that in immortalized, non-transformed cells, ectopic co-expression of Akt2 and ASAH1 is significantly more effective than expression of each gene alone at inducing cell invasion and at conferring resistance to apoptosis. Consistent with these observations, siRNA-mediated depletion of both Akt2 and ASAH1 is much more potent than depleting each alone at inhibiting cell viability/proliferation and cell invasion. Furthermore, pharmacological inhibitors of Akt (TCN or MK-2206) and ASAH1 (B13) synergize to inhibit cell viability/proliferation, and combinations of these drugs are more effective than single-agent treatments at inhibiting cell invasion. Taken together, the results suggest that these two enzymes cooperate to induce malignant transformation and warrant further preclinical studies to evaluate the potential of combining inhibitors of Akt and ASAH1 to treat cancer.
authors.affiliation: Drug Discovery Department and Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Berndt
authors.forename: Ronil
authors.initials: R
authors.lastname: Patel
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Maria E
authors.initials: ME
authors.lastname: Balasis
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000577:Amides / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000577:Amides; D000903:Antibiotics, Antineoplastic; C505590:DeltaPH-AKT2 protein; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; D010446:Peptide Fragments; D011412:Propanolamines; D034741:RNA, Small Interfering; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; C526693:ASAH1 protein, human; D055573:Acid Ceramidase
keywords: Akt; B13; MK-2206; TCN; acid ceramidase; apoptosis; cell invasion; drug synergy; synthetic lethal interaction