Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death

Z, Li; Zhang, J; Z, Liu; Cw, Woo; Cj, Thiele

doi:10.1038/sj.cdd.4401983

Cited by 65 publications

(58 citation statements)

References 44 publications

(72 reference statements)

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“…Thus, these data imply that the reduction of Bim expression might be the reason for the apoptosis-resistant phenotype of TACC3-depleted cells. In agreement with this hypothesis are recent reports demonstrating that Bim is an important mediator of apoptosis induced by microtubule-interfering agents such as PTX (Janssen et al, 2007;Li et al, 2007), although contrary reports also exist (Czernick et al, 2009). …”

Section: Resultssupporting

confidence: 70%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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Section: Resultssupporting

confidence: 70%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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“…BDNF-mediated protection from chemotherapy was also mediated by the down-regulation of Bim, a pro-apoptotic protein that facilitates mitochondrial-mediated or intrinsic apoptosis (5,36). Furthermore, it is possible that BDNF promotes resistance to extrinsic apoptosis by up-regulating production of proteins associated with halting the activation of transmembrane death receptors.…”

Section: Bdnf: a Governor Of Chemotherapeutic Sensitivitymentioning

confidence: 99%

BDNF: An Oncogene or Tumor Suppressor?

Radin

Patel

2017

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“…Cells and Cell Culture Stable TrkB-expressing cell line TB8 and NGP-TrkB cells (20) were cultured in RPMI 1640 (Mediatech, Inc.) containing 10% fetal bovine serum (FBS), 2 mmol/L glutamine, and antibiotics at 37jC in 5% CO 2 incubator. To maintain TrkB selection, neuroblastoma cells were cultured in puromycin (0.5Ag/mL; Sigma-Aldrich Inc.).…”

Section: Methodsmentioning

confidence: 99%

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

Tan

Thiele

2007

Molecular Cancer Therapeutics

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Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brainderived 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-3B (GSK-3B), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3B in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3B, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3B, LiCl, GSK-3B inhibitor VII, kenpaullone, or a GSK-3B -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-3B S9A9 caused a 10% to 15% decrease in cell survival. Using realtime, 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-3B in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3B contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy. [Mol Cancer Ther 2007;6(12):3113 -21]

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Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death

Cited by 65 publications

References 44 publications

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

BDNF: An Oncogene or Tumor Suppressor?

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

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