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Research Articles: Therapeutics, Targets, and Development

Inactivation of glycogen synthase kinase-3β contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells

Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Carol J. Thiele, Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive MSC-1928, Bldg. 10/CRC 1-3940, Bethesda, MD 20892. Phone: 301-496-1543; Fax: 301-451-7052. E-mail: ct47a{at}nih.gov

Abstract

Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with poor prognosis. Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. To study targets of PI3K/Akt that mediate protection from chemotherapy, we focused on glycogen synthase kinase-3β (GSK-3β), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3β in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3β, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3β, LiCl, GSK-3β inhibitor VII, kenpaullone, or a GSK-3β–targeted small interfering RNA (siRNA) resulted in a 15% to 40% increase in neuroblastoma cell survival after cytotoxic treatment. Transfection of neuroblastoma cells with a constitutively active GSK-3β S9A9 caused a 10% to 15% decrease in cell survival. Using real-time, dynamic measurements of cell survival, we found that 6 to 8 h after etoposide treatment was the period during which critical events regulating the induction of cell death or BDNF/TrkB-induced protection occurred. During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3β in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3β contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy. [Mol Cancer Ther 2007;6(12):3113–21]

Grant support: NIH Intramural Research Program of Center for Cancer Research at the National Cancer Institute.

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¹ Unpublished data.

Received 2/27/07; revised 9/18/07; accepted 10/24/07.