title: Growth inhibition by bupivacaine is associated with inactivation of ribosomal protein S6 kinase 1.
abstract: Bupivacaine is an amide type long acting local anesthetic used for epidural anesthesia and nerve blockade in patients. Use of bupivacaine is associated with severe cytotoxicity and apoptosis along with inhibition of cell growth and proliferation. Although inhibition of Erk, Akt, and AMPK seemingly appears to mediate some of the bupivacaine effects, potential downstream targets that mediate its effect remain unknown. S6 kinase 1 is a common downstream effector of several growth regulatory pathways involved in cell growth and proliferation known to be affected by bupivacaine. We have accordingly attempted to relate the growth inhibitory effects of bupivacaine with the status of S6K1 activity and we present evidence that decrease in cell growth and proliferation by bupivacaine is mediated through inactivation of S6 kinase 1 in a concentration and time dependent manner. We also show that ectopic expression of constitutively active S6 kinase 1 imparts substantial protection from bupivacaine induced cytotoxicity. Inactivation of S6K1 though associated with loss of putative mTOR mediated phosphorylation did not correspond with loss of similar phosphorylations in 4EBP1 indicating that S6K1 inhibition was not mediated through inactivation of mTORC1 signaling pathway or its down regulation.
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Mushtaq Ahmad
authors.initials: MA
authors.lastname: Beigh
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Mehvish
authors.initials: M
authors.lastname: Showkat
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Basharat
authors.initials: B
authors.lastname: Bashir
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Asma
authors.initials: A
authors.lastname: Bashir
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Mahboob ul
authors.initials: Mu
authors.lastname: Hussain
authors.affiliation: Department of Biotechnology, Science Block, University of Kashmir, Srinagar J&K 190006, India ; Department of Biotechnology and Bioinformatics, University of Kashmir, Srinagar J&K 190006, India.
authors.forename: Khurshid Iqbal
authors.initials: KI
authors.lastname: Andrabi
mesh_terms: D000767:Anesthesia, Epidural; D017209:Apoptosis / Q000187:drug effects; D002045:Bupivacaine / Q000008:administration & dosage* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002045:Bupivacaine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C467003:RPS6KC1 protein, human