title: Sustained activation of the extracellular signal-regulated kinase pathway protects cells from photofrin-mediated photodynamic therapy.
abstract: Photodynamic therapy (PDT) is a cancer therapy in which a photosensitizer selectively accumulates in tumor cells and is subsequently activated by light of a specific wavelength. The activation of the photosensitizer leads to cytotoxic photoproducts that result in tumor regression. PDT can lead to several cellular responses including cell cycle arrest, necrosis, and apoptosis, as well as trigger many signaling pathways. It has been suggested that extracellular signal-activated protein kinases (ERKs), one subfamily of mitogen-activated protein kinases, play a crucial role in the cellular response to radiation therapy and chemotherapy. However, the role of ERKs in the cell survival after PDT is less clear. We have examined the response of the extracellular signal-regulated kinase ERK1/2 in PDT-resistant (LFS087) and PDT-sensitive (GM38A) cells after Photofrin-mediated PDT. ERK1/2 activity was induced rapidly in both cell types after PDT. The PDT-induced ERK1/2 activity was transient in GM38A cells and by 3 h had returned to a level significant lower than basal levels, whereas the induction of ERK1/2 was sustained in LFS087 cells and lasted for at least 11 h. Blocking of the sustained ERK activity with PD98059, an inhibitor of mitogen-activated protein/ERK kinase, significantly decreased cell survival of LFS087 after PDT. PDT also induced the expression of mitogen-activated protein kinase phosphatase, MKP-1, but reduced Raf-1 protein levels in both cell types. In GM38A cells, the substantially induced levels of MKP-1 correlated with the transient activation of ERK1/2 by PDT, and both basal and induced levels of MKP-1 were substantially greater in GM38 compared with Li Fraumeni syndrome cells. These observations suggest that sustained ERK1/2 activation protects cells from Photofrin-mediated phototoxicity and that the duration of ERK1/2 activation is regulated by MKP-1. In addition, the activation of ERK1/2 by Photofrin-mediated PDT is Raf-1 independent.
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D017323:Dihematoporphyrin Ether / Q000494:pharmacology*; D004351:Drug Resistance; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D016864:Li-Fraumeni Syndrome / Q000201:enzymology / Q000473:pathology; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D010778:Photochemotherapy; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017874:Immediate-Early Proteins; D017323:Dihematoporphyrin Ether; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one