title: Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells.
abstract: Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.
authors.affiliation: a Center for Drug Discovery; Northeastern University; Boston, MA USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Changyan
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D056744:Cyclin B1 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D056744:Cyclin B1; D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D018631:ras Proteins
keywords: Chk1; NF1; PKC; mitotic catastrophe; mitotic exit checkpoint