RRC ID 79327
Author Zeng L, Kizaka-Kondoh S, Itasaka S, Xie X, Inoue M, Tanimoto K, Shibuya K, Hiraoka M.
Title Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions.
Journal Cancer Sci
Abstract Paclitaxel (PTX) is an anticancer drug that is effective against a wide range of solid tumors. The effect of PTX on two human lung cancer cell lines, PC14PE6 and NCI-H441 cells, was examined in an orthotopically transplanted animal model with an in vivo imaging devise. Although PTX effectively suppressed tumor growth and improved survival rate in NCI-H441, it did not influence these in PC14PE6. In vitro experiments confirmed that PC14PE6 cells are resistant to PTX under normoxic conditions and that both cell lines were resistant to PTX under hypoxic conditions. It was found that the expression level of endogenous hypoxia inducible factor (HIF)-1alpha in PC14PE6 is much higher than that in NCI-H441 cells under normoxic conditions. Furthermore, sensitivity to PTX in these cell lines was reversed when HIF-1alpha expression was decreased by siRNA specific to HIF-1alpha in PC14PE6 and increased by overexpression of the exogenous HIF-1alpha gene in NCI-H441. These results suggest that HIF-1 influences the PTX sensitivity of these cells. The authors further examined beta-tubulin, a target molecule of PTX, with western blotting and immunohistochemical analysis in these cells. The expression level of beta-tubulin was comparable in these cells under both normoxic and hypoxic conditions while the distribution of beta-tubulin and cell morphology were changed according to HIF-1alpha expression levels, suggesting that HIF-1 influences the conformation and dynamics of microtubules. These data support the potential development of HIF-1 targeted approaches in combination with PTX, where drug resistance tends to contribute to treatment failure.
Volume 98(9)
Pages 1394-401
Published 2007-9-1
DOI 10.1111/j.1349-7006.2007.00537.x
PII CAS537
PMID 17608771
MeSH Animals Cell Line Cell Line, Tumor Drug Resistance, Neoplasm Drug Screening Assays, Antitumor* Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / physiology* Lung Neoplasms / drug therapy Lung Neoplasms / metabolism* Lung Neoplasms / pathology* Male Mice Mice, Inbred BALB C Mice, Nude Paclitaxel / pharmacology* Protein Conformation Tubulin / biosynthesis Tubulin / chemistry Tubulin / genetics Tubulin / physiology Tubulin Modulators / pharmacology*
IF 4.966
Resource
Human and Animal Cells 10T1/2(RCB0247)