Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells.
The Hedgehog (Hh) pathway regulates cell proliferation and survival and contributes to tumorigenesis. We investigated the expression and function of this pathway in B-cell chronic lymphocytic leukemia (CLL) cells and in healthy B lymphocytes. Profiling of cognate Hh pathway members revealed reduced expression of two key Hh signaling effectors, Smoothened (SMOH) and GLI, in CLL cells, whereas transcription levels of other investigated members resembled normal B-lymphocyte levels. Examining the functional role of SMOH and GLI in cell survival, we found that CLL cells were hardly sensitive toward specific SMOH inhibition, but showed an unspecific decline in cell viability in response to high concentrations of the SMOH antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT61 reduced expression of the target gene Patched and preferentially decreased the viability of malignant cells. Specific RNA interference knockdown experiments in a CLL-derived cell line confirmed the autonomous role of GLI in malignant cell survival. GANT61-induced apoptosis in primary leukemic cells was partly attenuated by protective stromal cells, but not soluble sonic hedgehog ligand. In summary, our data show a downregulation of the classical Hh pathway in CLL and suggest an intrinsic SMOH-independent role of GLI in the ex vivo survival of CLL cells.
Desch
P
P
Laboratory for Immunological and Molecular Cancer Research, IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria.
Asslaber
D
D
Kern
D
D
Schnidar
H
H
Mangelberger
D
D
Alinger
B
B
Stoecher
M
M
Hofbauer
S W
SW
Neureiter
D
D
Tinhofer
I
I
Aberger
F
F
Hartmann
T N
TN
Greil
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
C551027:GANT 61; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine