Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism.
Lung cancer is a leading cause of cancer-related death in the United States. For this reason we chose to study the specific cellular effects that one chemotherapeutic agent, paclitaxel, has on lung carcinoma. In addition to its known mechanism of action, which is to stabilize microtubules, paclitaxel has been shown to have other interesting and relevant cellular effects. In this report, we demonstrate that a subset of human lung carcinoma cell lines respond to paclitaxel treatment with an up to a fivefold increase in the production of interleukin-8 (IL-8). We demonstrate that this increased production is specific to IL-8 but not to other chemokines, and is both dose- and time-dependent. Increased IL-8 mRNA is seen as early as 45 min with a peak at 4 h after paclitaxel treatment. This increase in mRNA is due to transcriptional activation because actinomycin D treatment blocked the increase. Paclitaxel also activates the mitogen-activated protein kinase family member, JNK1, in dose-dependent fashion. IL-8 enhancement is completely abolished with the use of an inhibitor of NF-kappaB, the super-repressor IkappaB. Similar results were obtained upon the inhibition of AP-1 activation with the MEK1/2 inhibitor, U0126. By gaining a better understanding of the differences in cellular response to paclitaxel chemotherapy, these findings might lead to either improved patient selection or to the development of adjuvant therapy targeted at specific-cell signaling proteins.
Collins
T S
TS
University of North Carolina Lineberger Comprehensive Cancer Center, Department of Surgery, Chapel Hill 27599-7295, USA.
Lee
L F
LF
Ting
J P
JP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D016209:Interleukin-8; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel