Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma.
Mantle cell lymphoma (MCL) has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival of only 3 to 4 years. Therefore, a better understanding of the underlying mechanisms that regulate MCL proliferation/survival is needed to develop an effective therapy. Because sonic hedgehog (Shh)-GLI signaling has been shown to be important in the proliferation and survival of several cancers, and no such information is available for MCL, this study was undertaken. Our results show that the molecules associated with Shh-GLI signaling, such as PTCH and SMO receptors, and GLI1 and GLI2 target transcription factors were expressed in the human MCL cell lines and primary MCL cells from patients. Perturbation of this signaling in the presence of exogenous Shh/cyclopamine significantly (P < 0.001) influenced the proliferation of JVM2 MCL cells. Furthermore, down-regulation of GLI transcription factors using antisense oligonucleotides not only resulted in significantly (P < 0.001) decreased proliferation of the MCL cells but also significantly (P < 0.05) increased their susceptibility to chemotherapeutic drug, doxorubicin. Also, down-regulation of GLI decreased cyclin D1 and BCL2 transcript levels, which suggests that these key molecules might be regulated by GLI in MCL. Thus, our results indicate a significant role for Shh-GLI signaling in the proliferation of MCL, and molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL.
Hegde
Ganapati V
GV
Department of Genetics, Cell Biology, and Anatomy, Center for Research in Leukemia and Lymphoma, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA.
Munger
Corey M
CM
Emanuel
Katy
K
Joshi
Avadhut D
AD
Greiner
Timothy C
TC
Weisenburger
Dennis D
DD
Vose
Julie M
JM
Joshi
Shantaram S
SS
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D019938:Cyclin D1; D004317:Doxorubicin