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BIN1 tumor suppressor regulates Fas/Fas ligand-mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma
S Esmailzadeh1, Y Huang2, M-W Su3
11] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL.
Insights
Bridging integrator 1 (BIN1) suppresses tumors by restoring apoptosis in cutaneous T-cell lymphoma (CTCL). BIN1 deficiency promotes CTCL by resisting apoptosis, making BIN1 and c-FLIP potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Bridging integrator 1 (BIN1) is a tumor suppressor involved in DNA repair, cell-cycle control, and apoptosis.
- BIN1 downregulation is observed in solid tumors, but its role in lymphomagenesis is unknown.
- BIN1 transcript levels are significantly reduced in Sezary syndrome (SS), a type of cutaneous T-cell lymphoma (CTCL).
Purpose of the Study:
- To investigate the role of BIN1 in the pathogenesis of CTCL.
- To determine if BIN1 can restore apoptosis and inhibit tumor growth in CTCL.
- To explore the therapeutic potential of BIN1 and c-FLIP in CTCL.
Main Methods:
- Restored BIN1 expression in CTCL cells and assessed effects on proliferation, apoptosis, and tumorigenic activity.
- Investigated the mechanism by which BIN1 affects apoptosis, focusing on c-FLIP and caspase activation.
- Analyzed BIN1 and c-FLIP expression in primary CTCL patient samples and correlated with survival rates.
Main Results:
- Restored BIN1 expression reduced CTCL cell proliferation, increased apoptosis, and inhibited tumor growth in vivo.
- BIN1 restoration downregulated c-FLIP expression, activated caspases, and sensitized cells to Fas/FasL-induced apoptosis.
- Reduced BIN1 and increased c-FLIP expression were observed in primary CTCL samples, correlating with poorer survival.
Conclusions:
- BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP in CTCL.
- BIN1 deficiency contributes to apoptosis resistance and CTCL pathogenesis.
- BIN1 and c-FLIP are potential therapeutic targets for CTCL.
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