BACKGROUND: Components of the mitogen-activated protein kinase (MAPK) cascade have been implicated in apoptotic regulation. This study used gene expression profiling analysis to identify and implicate mitogen-activated protein kinase kinase (MEK5)-BMK1 (big mitogen-activated kinase-1)/extracellular signal related protein kinase (ERK5) pathway as a novel target involved in chemoresistance. METHODS: Differential gene expression between apoptotically sensitive (APO+) and apoptotically resistant (APO-) MCF-7 cell variants was determined by using microarray and confirmed by reverse transcriptase- polymerase chain reaction (RT-PCR). An apoptotic/viability reporter gene assay was used to deter-mine the effects of the transfection of a dominant-negative mutant of BMK1 (BMK1/DN) in conjunction with apoptotic-inducing agents (etoposide, tumor necrosis factor-alpha [TNF], or TNF-related apoptosis-inducing ligand [TRAIL]), with or without phorbol ester (PMA). RESULTS: Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells. Overexpression of MEK5 was confirmed by using RT-PCR analysis. Expression of BMK1/DN alone resulted in a dose-dependent increase in cell death versus control (P <.05). In addition, BMK1/DN enhanced the sensitivity of MCF-7 cells to treatment-induced cell death (P <.05). The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN. However, only TRAIL-induced activity suppression reached statistical significance (P <.05). CONCLUSIONS: The overexpression of MEK5 in APO- MCF-7 breast carcinoma cells shows that this MAPK signaling protein represents a potent survival molecule. Molecular inhibition of MEK5 signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens.
BACKGROUND: Components of the mitogen-activated protein kinase (MAPK) cascade have been implicated in apoptotic regulation. This study used gene expression profiling analysis to identify and implicate mitogen-activated protein kinase kinase (MEK5)-BMK1 (big mitogen-activated kinase-1)/extracellular signal related protein kinase (ERK5) pathway as a novel target involved in chemoresistance. METHODS: Differential gene expression between apoptotically sensitive (APO+) and apoptotically resistant (APO-) MCF-7 cell variants was determined by using microarray and confirmed by reverse transcriptase- polymerase chain reaction (RT-PCR). An apoptotic/viability reporter gene assay was used to deter-mine the effects of the transfection of a dominant-negative mutant of BMK1 (BMK1/DN) in conjunction with apoptotic-inducing agents (etoposide, tumor necrosis factor-alpha [TNF], or TNF-related apoptosis-inducing ligand [TRAIL]), with or without phorbol ester (PMA). RESULTS: Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells. Overexpression of MEK5 was confirmed by using RT-PCR analysis. Expression of BMK1/DN alone resulted in a dose-dependent increase in cell death versus control (P <.05). In addition, BMK1/DN enhanced the sensitivity of MCF-7 cells to treatment-induced cell death (P <.05). The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN. However, only TRAIL-induced activity suppression reached statistical significance (P <.05). CONCLUSIONS: The overexpression of MEK5 in APO- MCF-7 breast carcinoma cells shows that this MAPK signaling protein represents a potent survival molecule. Molecular inhibition of MEK5 signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens.
Authors: Van T Hoang; Thomas J Yan; Jane E Cavanaugh; Patrick T Flaherty; Barbara S Beckman; Matthew E Burow Journal: Cancer Lett Date: 2017-01-30 Impact factor: 8.679
Authors: James W Antoon; Martin D White; William D Meacham; Evelyn M Slaughter; Shannon E Muir; Steven Elliott; Lyndsay V Rhodes; Hasina B Ashe; Thomas E Wiese; Charles D Smith; Matthew E Burow; Barbara S Beckman Journal: Endocrinology Date: 2010-09-22 Impact factor: 4.736
Authors: Qingkai Yang; Xianming Deng; Bingwen Lu; Michael Cameron; Colleen Fearns; Matthew P Patricelli; John R Yates; Nathanael S Gray; Jiing-Dwan Lee Journal: Cancer Cell Date: 2010-09-14 Impact factor: 31.743