+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Up-regulation of pro-apoptotic protein Bim and down-regulation of anti-apoptotic protein Mcl-1 cooperatively mediate enhanced tumor cell death induced by the combination of ERK kinase (MEK) inhibitor and microtubule inhibitor

Up-regulation of pro-apoptotic protein Bim and down-regulation of anti-apoptotic protein Mcl-1 cooperatively mediate enhanced tumor cell death induced by the combination of ERK kinase (MEK) inhibitor and microtubule inhibitor

Journal of Biological Chemistry 287(13): 10289-10300

Blockade of the ERK signaling pathway by ERK kinase (MEK) inhibitors selectively enhances the induction of apoptosis by microtubule inhibitors in tumor cells in which this pathway is constitutively activated. We examined the mechanism by which such drug combinations induce enhanced cell death by applying time-lapse microscopy to track the fate of individual cells. MEK inhibitors did not affect the first mitosis after drug exposure, but most cells remained arrested in interphase without entering a second mitosis. Low concentrations of microtubule inhibitors induced prolonged mitotic arrest followed by exit of cells from mitosis without division, with most cells remaining viable. However, the combination of a MEK inhibitor and a microtubule inhibitor induced massive cell death during prolonged mitosis. Impairment of spindle assembly checkpoint function by RNAi-mediated depletion of Mad2 or BubR1 markedly suppressed such prolonged mitotic arrest and cell death. The cell death was accompanied by up-regulation of the pro-apoptotic protein Bim (to which MEK inhibitors contributed) and by down-regulation of the anti-apoptotic protein Mcl-1 (to which microtubule and MEK inhibitors contributed synergistically). Whereas RNAi-mediated knockdown of Bim suppressed cell death, stabilization of Mcl-1 by RNAi-mediated depletion of Mule slowed its onset. Depletion of Mcl-1 sensitized tumor cells to MEK inhibitor-induced cell death, an effect that was antagonized by knockdown of Bim. The combination of MEK and microtubule inhibitors thus targets Bim and Mcl-1 in a cooperative manner to induce massive cell death in tumor cells with aberrant ERK pathway activation.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 056773990

Download citation: RISBibTeXText

PMID: 22270368

DOI: 10.1074/jbc.m111.319426

Related references

Protein kinase inhibitor attenuates apoptotic cell death induced by amyloid beta protein in culture of the rat cerebral cortex. Neuroscience Letters 203(3): 175-178, 1996

Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic suppressor Raf kinase inhibitor protein via Yin Yang 1 inhibition and death receptor 5 up-regulation. Journal of Immunology 179(8): 5441-5453, 2007

Synergistic action of piroxicam on the eicosapentaenoic acid-induced apoptosis is associated with enhanced down-regulation of anti-apoptotic Bcl-2 expression but not promoted activation of pro-apoptotic Bid protein. Oncology Reports 11(1): 225-230, 2004

Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proceedings of the National Academy of Sciences of the United States of America 98(15): 8662-8667, 2001

Apoptotic cell death of protein kinase inhibitor-induced polyploid cells in a cultured sarcoma cell line. Molecular Biology of the Cell 7(Suppl. ): 519A, 1996

The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation. Journal of Pathology 213(2): 170-179, 2007

Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser(87) to suppress apoptotic cell death. Psychogeriatrics 11(2): 90-97, 2011

Potentiation of tumor necrosis factor-alpha-induced tumor cell apoptosis by a small molecule inhibitor for anti-apoptotic protein hPEBP4. Journal of Biological Chemistry 285(16): 12241-7, 2010

Transcriptional regulation of pro-apoptotic protein kinase Cdelta: implications for oxidative stress-induced neuronal cell death. Journal of Biological Chemistry 286(22): 19840-19859, 2011

Guanylyl cyclase inhibitors NS2028 and ODQ and protein kinase G (PKG) inhibitor KT5823 trigger apoptotic DNA fragmentation in immortalized uterine epithelial cells: anti-apoptotic effects of basal cGMP/PKG. Molecular Human Reproduction 9(12): 775-783, 2003

Changes in expression and regulation of the cyclin dependent kinase inhibitor p27 after in vivo and in vitro spinal cord injury Role in apoptotic cell death. Journal of Neurotrauma 17(10): 954, 2000

Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. Journal of Biological Chemistry 279(48): 50295-50301, 2004

Efficacy of combination treatment of the inhibitor of phosphatidyl inositol-3-kinase/protein kinase B pathway BEZ235 and the inhibitor of extracellular regulated protein kinase/mitogen-activated protein kinase pathway U0126 in a tumor cell model. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae 35(5): 530-534, 2013

Protection from apoptotic cell death by cilostazol, phosphodiesterase type III inhibitor, via cAMP-dependent protein kinase activation. Pharmacological Research 54(4): 261-267, 2006

Potentiation of kinesin spindle protein inhibitor-induced cell death by modulation of mitochondrial and death receptor apoptotic pathways. Cancer Research 67(1): 237-245, 2007