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Title of Journal: Apoptosis

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Abbravation: Apoptosis

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Springer US

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DOI

10.1002/cber.19230560865

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1573-675X

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Role of Bim in apoptosis induced in H460 lung tumo

Authors: G Mendez C Policarpi C Cenciarelli C Tanzarella A Antoccia
Publish Date: 2011/06/14
Volume: 16, Issue: 9, Pages: 940-949
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Abstract

The BH3only Bcl2 subfamily member Bim is a well known apoptosis promoting protein However the mechanisms upstream of mitochondrion membrane permeability by which Bim is involved in apoptosis have been poorly investigated particularly in response to agents capable of interfering with the cytoskeleton architecture and arresting cells in mitosis Based on the observation that Bim is sequestered on the microtubulearray by interaction with the light chain of dynein we have investigated upon depolymerisation whether Bim could be involved in the commitment of apoptosis With this purpose H460 Non Small Lung Cancer Cells NSLC were treated with the microtubule damaging agent combretastatinA4 CA4 75 nM 8–48 h and various parameters were investigated Upon treatment cells arrested in mitosis and died through a caspase3dependent mitotic catastrophe Transient knock down of Bim drastically reduced apoptosis indicating that this protein was involved in cell death as induced by microtubules disorganisation In response to increasing conditions of microtubules depolymerisation we found that the protein level of Bim was strongly upregulated in a timedependent manner at transcriptional level Furthermore Bim was released from microtubuleassociated components Bim was translocated to mitochondria even in a condition of protein synthesis inhibition where it showed a markedly increased interaction with Bcl2 In turn the fraction of Bax bound to Bcl2 decreases in response to treatment thereby indicating that Bim possibly promotes Bax release from the prosurvival protein Bcl2 Overall we demonstrated that Bim is required for the CA4induced cell death in the H460 lung cancer cell line via activation of the mitochondrial signalling pathway Defining the contribution of Bim to the mechanism of apoptosis may offer some different clues in view of developing new strategies for chemotherapy with CA4 underlining the relevance of the cytoskeleton integrity in the apoptotic response

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