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AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell
response and resistance to cetuximab
#MMPMID25871473
Li X
; Lu Y
; Lu H
; Luo J
; Hong Y
; Fan Z
Oncotarget
2015[May]; 6
(13
): 11507-18
PMID25871473
show ga
We previously reported that cetuximab, an EGFR-blocking antibody, inhibits cancer
metabolism via downregulation of HIF-1? 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.
|*Drug Resistance, Neoplasm
[MESH]
|AMP-Activated Protein Kinase Kinases
[MESH]
|AMP-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism
[MESH]
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