title: Akt, 14-3-3ζ, and vimentin mediate a drug-resistant invasive phenotype in diffuse large B-cell lymphoma.
abstract: Development of resistance to the CHOP chemotherapeutic regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) remains a major cause of treatment failure and mortality in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL). We established CHOP-resistant DLBCL cells as a model system to investigate molecular mechanisms involved in multidrug resistance. Two-dimensional differential in-gel (DIGE) analysis identified 10 differentially expressed proteins between CHOP-sensitive and -resistant DLBCL cells that play roles in glycolysis (triosephosphate isomerase-1, enolase-1), cytoskeletal structure (ezrin, vimentin, tubulin-specific chaperone B), purine biosynthesis (serine hydroxymethyltransferase), calcium binding (sorcin), and apoptosis (p53, 14-3-3ζ, Akt). Akt, 14-3-3ζ, and vimentin were up-regulated in CHOP-resistant DLBCL cells. We showed previously that siRNA-mediated knockdown of 14-3-3ζ reversed CHOP resistance in DLBCL cells (Maxwell et al., J Biol Chem 2009;284:22379-22389). Here we show that chemical inhibition of Akt overcomes CHOP resistance in DLBCL cells. CHOP-resistant cells exhibited a five-fold greater ability to invade collagen matrices compared with CHOP-sensitive cells. Knockdown of vimentin by siRNA or withaferin A repressed the invasiveness of CHOP-resistant cells in collagen matrices. Increased expressions of Akt, 14-3-3ζ, and vimentin were observed by Western blotting in primary DLBCL tissues relative to normal lymphatic tissue. The data implicate activation of an Akt-14-3-3ζ signaling pathway in promoting a multidrug-resistant phenotype associated with a vimentin-dependent invasive behavior in DLBCL cells.
authors.affiliation: Department of Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA. smaxwell@medicine.tamhsc.edu
authors.forename: Steve A
authors.initials: SA
authors.lastname: Maxwell
authors.forename: Evan M
authors.initials: EM
authors.lastname: Cherry
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Bayless
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D011241:Prednisone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D048948:14-3-3 Proteins; D034741:RNA, Small Interfering; D014746:Vimentin; C482984:YWHAH protein, human; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D051057:Proto-Oncogene Proteins c-akt; D011241:Prednisone