Frequent requirement of hedgehog signaling in non-small cell lung carcinoma.
Although it had previously been suggested that the hedgehog (HH) pathway might be activated in some lung tumors, the dependence of non-small cell lung carcinomas (NSCLC) for HH activity had not been comprehensively studied. During a screen of a panel of 60 human tumor cell lines with an HH antagonist, we observed that the proliferation of a subset of NSCLC cell lines was inhibited. These NSCLC cell lines express HH, as well as key HH target genes, consistent with them being activated through an autocrine mechanism. Interestingly, we also identified a number of NSCLC cell lines that express high levels of the downstream transcription factor GLI1 and harbor enhanced levels of HH activity, but appear insensitive to known HH antagonists. We hypothesized that the high levels of GLI1 in these cells would function downstream of the HH antagonist target, allowing them to bypass the antagonist-mediated block in proliferation. Consistent with this hypothesis, when the levels of GLI1 are knocked down in such cells, they become sensitive to these inhibitors. We go on to show that a large percentage of primary NSCLC samples express GLI1, consistent with constitutive activation of the HH pathway in these samples. Taken together, these results establish the involvement of the HH signaling pathway in a subset of NSCLCs.
Yuan
Z
Z
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Goetz
J A
JA
Singh
S
S
Ogden
S K
SK
Petty
W J
WJ
Black
C C
CC
Memoli
V A
VA
Dmitrovsky
E
E
Robbins
D J
DJ
D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D045325:HCT116 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D053823:Hedgehog Proteins; D010879:Piperazines; D011720:Pyrazoles; C468919:SANT-1 compound