title: Modulation of Raf/MEK/ERK kinase activity does not affect the chemoresistance profile of advanced prostate cancer cells.
abstract: The Raf/MEK/ERK signaling cascade has been extensively studied for its roles in growth and differentiation of a variety of cell types. Confliciting evidence exists regarding the function of classical MAPK signaling with regards to the development of chemotherapeutic drug resistance; some reports describe an pro-survival role, whereas others have suggested that activation of Raf/MEK/ERK is essential for drug-induced death. To elucidate the importance of MAPK signaling in the development of advanced prostate cancer drug resistance, DU145 and PC3 prostate cells were stably-infected/transfected with constitutively-activated mutants of both Raf-1 and B-Raf. Results from MTT analyses suggested that activation of either Raf-1 or B-Raf is inconsequential in prostate cancer chemoresistance. To confirm these findings, the MAPK signal transduction cascade was activated with EGF and response to doxorubicin or paclitaxel was measured in the presence/absence of the MEK-specific inhibitor, U0126. These results showed that inhibition of signals transduced by the MAPK pathway are insufficient to affect the chemoresistance profile of advanced prostate cancer cells. Together, these data demonstrate that the response of prostatic tumors to the chemotherapeutic compounds doxorubicin and paclitaxel is independent of Raf/MEK/ERK signaling.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Lee
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*
chemical_list: D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases