Abstract
We previously reported that cetuximab, an EGFR-blocking antibody, inhibits cancer metabolism via downregulation of HIF-1α and reverses the Warburg effect in cancer cells. Here, we report that inhibition of HIF-1 transcriptional activity by cetuximab does not necessarily lead to successful inhibition of cell proliferation. In several head and neck squamous cell carcinoma (HNSCC) cell lines, we observed a pattern of oscillating decrease and increase of intracellular ATP level after cetuximab treatment, and the magnitude and kinetics of which varied by cell line and appeared to be linked to the extent of cellular response to cetuximab. In HNSCC cells with low basal level of AMPK activity and that responded to cetuximab-induced growth inhibition, there was a transient, LKB1-dependent activation of AMPK. In contrast, HNSCC cells that had a high basal level of AMPK activity were less sensitive to cetuximab-induced growth inhibition despite effective inhibition of EGFR downstream signaling by cetuximab. Knockdown or inhibition of AMPK markedly enhanced response to cetuximab via induction of apoptosis. These findings indicate that a transient activation of AMPK is an early metabolic marker of cellular response to cetuximab and that high and sustained AMPK activity is an important mechanism by which cancer cells survive cetuximab treatment.
Highlights
Epidermal growth factor receptor (EGFR)-mediated cell signaling is aberrantly regulated in many types of human malignancy of epithelial origin [1]
The level of HIF-1α in these cell lines was quantitatively linked to the transcriptional activity of Hypoxia-inducible factor-1 (HIF-1) in these cells measured by a HIF1 luciferase reporter assay, and the decline in HIF-1α level upon cetuximab treatment was accompanied by a corresponding decline in HIF-1 transcriptional activity (Figure 1B)
A cell proliferation assay showed that whereas proliferation of HN5 and FaDu cells was substantially inhibited after a 5-day culture in the presence of cetuximab, proliferation of UMSCC1 cells was only minimally inhibited by cetuximab treatment; the rate of inhibition of cell proliferation was only approximately 25% in UMSCC1 cells compared to approximately 50% in FaDu cells and greater than 80% in HN5 cells (Figure 1C)
Summary
Epidermal growth factor receptor (EGFR)-mediated cell signaling is aberrantly regulated in many types of human malignancy of epithelial origin [1]. Few studies have linked response and resistance to EGFR-targeted therapy to the status of cancer cell metabolism. We reported that cetuximab reverses the Warburg effect in cancer cells via inhibiting HIF-1regulated lactate dehydrogenase A [18]. Overexpression of a degradation-resistant HIF-1α mutant counteracted cetuximab-induced decline in intracellular ATP level and conferred resistance to cetuximab-induced G1-phase cellcycle arrest [18]. These findings provide an important mechanistic link between cetuximab-induced inhibition of cell proliferation and cetuximab-induced inhibition of metabolism in targeted cancer cells
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