Targeting of sonic hedgehog-GLI signaling: A potential strategy to improve therapy for mantle cell lymphoma

Ganapati V. Hegde, Corey M. Munger, Katy Emanuel, Avadhut D. Joshi, Timothy Charles Greiner, Dennis D. Weisenburger, Julie Marie Vose, Shantaram S Joshi

Research output: Contribution to journalArticle

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Abstract

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, downregulation 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.

Original languageEnglish (US)
Pages (from-to)1450-1460
Number of pages11
JournalMolecular cancer therapeutics
Volume7
Issue number6
DOIs
StatePublished - Oct 15 2008

Fingerprint

Mantle-Cell Lymphoma
Therapeutics
Survival
Transcription Factors
Down-Regulation
Antisense Oligonucleotides
Cyclin D1
B-Cell Lymphoma
Doxorubicin
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting of sonic hedgehog-GLI signaling : A potential strategy to improve therapy for mantle cell lymphoma. / Hegde, Ganapati V.; Munger, Corey M.; Emanuel, Katy; Joshi, Avadhut D.; Greiner, Timothy Charles; Weisenburger, Dennis D.; Vose, Julie Marie; Joshi, Shantaram S.

In: Molecular cancer therapeutics, Vol. 7, No. 6, 15.10.2008, p. 1450-1460.

Research output: Contribution to journalArticle

Hegde, Ganapati V. ; Munger, Corey M. ; Emanuel, Katy ; Joshi, Avadhut D. ; Greiner, Timothy Charles ; Weisenburger, Dennis D. ; Vose, Julie Marie ; Joshi, Shantaram S. / Targeting of sonic hedgehog-GLI signaling : A potential strategy to improve therapy for mantle cell lymphoma. In: Molecular cancer therapeutics. 2008 ; Vol. 7, No. 6. pp. 1450-1460.
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abstract = "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, downregulation 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.",
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