title: Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C.
abstract: Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg, SE.
authors.forename: Johan B
authors.initials: JB
authors.lastname: Fagman
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Yu
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.|The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Environmental Medicine, New York University, Tuxedo, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Changyan
authors.initials: C
authors.lastname: Chen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D005995:Glyceryl Ethers / Q000494:pharmacology; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008807:Mice, Inbred BALB C; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005995:Glyceryl Ethers; D025542:Neurofibromin 1; C059039:1-O-hexadecyl-2-O-methylglycerol; D000071877:Checkpoint Kinase 1; D011493:Protein Kinase C; D020725:ral GTP-Binding Proteins
keywords: Chk1; Nf1; Ral A; apoptosis; mitotic catastrophe