title: Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia.
abstract: Durable responses to imatinib monotherapy are rarely seen in aggressive forms of Philadelphia chromosome positive (Ph+) leukemias. To investigate the possible cause of treatment failure we examined the role of protein kinase C epsilon (PKCE), an oncogene highly implicated in the development of solid tumors and resistance to chemotherapy. We found high levels of PKCE transcripts in Ph+ acute lymphoblastic leukemia (ALL) cells from patients and cell lines, and imatinib resistant chronic myeloid leukemia, which were also less responsive to imatinib-induced apoptosis than Ph+ cells with lower PKCE expression. Furthermore, the siRNA-mediated knockdown or peptide inhibition of PKCE in Ph+ cells increased imatinib-induced apoptosis while overexpression of PKCE reduced imatinib-induced apoptosis, with concomitant increase in the pro-survival factor AKT. Our results suggest PKCE plays a protective role against apoptosis induced by BCR-ABL inhibition in Ph+ leukemias with high PKCE expression, such as Ph+ ALL.
authors.affiliation: a Blood, Stem Cell and Cancer Research Unit, St Vincent's Centre for Applied Medical Research, and Department of Hematology , St Vincent's Hospital , Sydney , Australia.
authors.forename: To Ha
authors.initials: TH
authors.lastname: Loi
authors.affiliation: a Blood, Stem Cell and Cancer Research Unit, St Vincent's Centre for Applied Medical Research, and Department of Hematology , St Vincent's Hospital , Sydney , Australia.
authors.forename: Pei
authors.initials: P
authors.lastname: Dai
authors.affiliation: a Blood, Stem Cell and Cancer Research Unit, St Vincent's Centre for Applied Medical Research, and Department of Hematology , St Vincent's Hospital , Sydney , Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Carlin
authors.affiliation: b Department of Hematology , Centre for Cancer Biology and University of Adelaide, Australia and Department of Hematology, Imperial College , London , UK.
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.affiliation: a Blood, Stem Cell and Cancer Research Unit, St Vincent's Centre for Applied Medical Research, and Department of Hematology , St Vincent's Hospital , Sydney , Australia.
authors.forename: David D F
authors.initials: DDF
authors.lastname: Ma
keywords: BCR-ABL; PKC epsilon; imatinib resistance