title: AKT Inhibition Promotes Nonautonomous Cancer Cell Survival.
abstract: Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this "AKT(low)" cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.lastname: Salony
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Xavier
authors.initials: X
authors.lastname: Solé
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Cleidson P
authors.initials: CP
authors.lastname: Alves
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Dey-Guha
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Laila
authors.initials: L
authors.lastname: Ritsma
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boukhali
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Ju H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Joeeta
authors.initials: J
authors.lastname: Chowdhury
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Shobha
authors.initials: S
authors.lastname: Vasudevan
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard & MIT, Cambridge, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Harvard-Ludwig Center for Cancer Research, Boston, Massachusetts. sridhar@mgh.harvard.edu.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D055432:Metabolomics; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt