title: Phenylbutyric acid induces the cellular senescence through an Akt/p21(WAF1) signaling pathway.
abstract: It has been well known that three sentinel proteins - PERK, ATF6 and IRE1 - initiate the unfolded protein response (UPR) in the presence of misfolded or unfolded proteins in the ER. Recent studies have demonstrated that upregulation of UPR in cancer cells is required to survive and proliferate. Here, we showed that long exposure to 4-phenylbutyric acid (PBA), a chemical chaperone that can reduce retention of unfolded and misfolded proteins in ER, induced cellular senescence in cancer cells such as MCF7 and HT1080. In addition, we found that treatment with PBA activates Akt, which results in p21(WAF1) induction. Interestingly, the depletion of PERK but not ATF6 and IRE1 also induces cellular senescence, which was rescued by additional depletion of Akt. This suggests that Akt pathway is downstream of PERK in PBA induced cellular senescence. Taken together, these results show that PBA induces cellular senescence via activation of the Akt/p21(WAF1) pathway by PERK inhibition.
authors.affiliation: Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Hag Dong
authors.initials: HD
authors.lastname: Kim
authors.forename: Chang-Young
authors.initials: CY
authors.lastname: Jang
authors.forename: Jeong Min
authors.initials: JM
authors.lastname: Choe
authors.forename: Jeongwon
authors.initials: J
authors.lastname: Sohn
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004722:Endoribonucleases; D008565:Membrane Proteins; D010654:Phenylbutyrates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C493956:CDKN1A protein, human; C075773:4-phenylbutyric acid; C403982:ERN2 protein, human