Functional cooperation between HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR
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Abstract
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<h5 class="section-title" id="d8682929e157">Objective</h5>
<p id="P2">Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important
transcription
factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun
are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal
growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental
cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine
kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation
of
<i>EGFR</i> have not been explored. In this study, we investigated the roles of HIF-1α
and c-Jun
in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating
mutation of
<i>EGFR</i>.
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<h5 class="section-title" id="d8682929e168">Materials and Methods</h5>
<p id="P3">Changes in HIF-1α protein and in total and phosphorylated c-Jun levels
in relation
to changes in total and phosphorylated EGFR levels before and after gefitinib treatment
were measured using Western blot analysis in NSCLC cells sensitive or resistant to
gefitinib. The impact of overexpression of a constitutively expressed HIF-1α (HIF-1α/ΔODD)
or a constitutively active c-Jun upstream regulator (SEK1 S220E/T224D mutant) on cell
response to gefitinib was also examined. The effect of pharmacological inhibition
of SEK1-JNK-c-Jun pathway on cell response to gefitinib was evaluated.
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<h5 class="section-title" id="d8682929e173">Results</h5>
<p id="P4">Downregulation of HIF-1α and total and phosphorylated c-Jun levels correlated
with
cell inhibitory response to gefitinib better than decrease in phosphorylated EGFR
did in NSCLC cells with intrinsic or acquired resistance to gefitinib. Overexpression
of HIF-1α/ΔODD or SEK1 S220E/T224D mutant conferred resistance to gefitinib. There
exists a positive feed-forward regulation loop between HIF-1 and c-Jun. The JNK inhibitor
SP600125 sensitized gefitinib-resistant NSCLC cells to gefitinib.
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<h5 class="section-title" id="d8682929e178">Conclusions</h5>
<p id="P5">HIF-1α and c-Jun functionally cooperate in development of resistance to
gefitinib
in NSCLC cells. The translational value of inhibiting HIF-1α/c-Jun cooperation in
overcoming resistance to EGFR TKI treatment of NSCLC cells with activating mutation
of
<i>EGFR</i> deserves further investigation.
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