title: The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells.
abstract: Raf-1 has an important role in cellular antiapoptosis. So far, there is no solid evidence that shows that Raf-1 mutation is associated with cancer development. In the course of further study of Raf-1 signaling, we have reported that Raf-1 hyperphosphorylation inhibits its kinase activity toward its downstream mitogen-activated protein kinase kinase 1/2 (MEK1/2) and proposed a model for negative feedback regulation of Raf-1. Here, we show that there is no hyperphosphorylation in some cancer cells, which results in increased kinase activity and enhances the antiapoptotic ability. Inhibition of either Raf-1 or ALG-2 (apoptosis-linked gene 2) expression results in apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase (ASK1/JNK) signaling activation, and cell sensitivity to chemotherapeutic reagents, indicating that inhibition of ASK1/JNK apoptotic signaling by Raf-1 is mediated by ALG-2. A previous report indicated that extracellular signal-regulated kinase 1/2 (ERK1/2) were responsible for Raf-1 hyperphosphorylation. However, our evidence shows that when ERK1/2 are activated and the Raf-1 gene is not mutated, Raf-1 is not hyperphosphorylated in these cells, indicating that ERK1/2 are not responsible for the Raf-1 hyperphosphorylation in these cancer cell lines. Surprisingly, we also found that Raf-1 is not a necessary kinase for MEK1/2 activation under normal tissue culture conditions, but is required for MEK1/2 activation under apoptosis-inducing conditions. Our research demonstrates that although Raf-1 gene is not mutated, an abnormality of Raf-1 kinase feedback regulation enhances its antiapoptotic function, and Raf-1 can still be a pharmaceutical target to increase chemotherapy or radiotherapy sensitivity in these cancer cells.
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Ma
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: B R
authors.initials: BR
authors.lastname: Cao
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: L P
authors.initials: LP
authors.lastname: Luo
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Gynecological Oncology, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: T
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Basic Research, Sichuan Cancer Hospital/Institute, Chengdu, China.
authors.forename: C M
authors.initials: CM
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; D004317:Doxorubicin; D019908:Proto-Oncogene Proteins c-raf