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Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.

ABSTRACT: TNFalpha and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFalpha and TRAIL. We show that inhibition of NF-kappaB or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFalpha or TRAIL. Inhibition of NF-kappaB by silencing TRAF2, by silencing RIP or by ectopic expression of IkappaB partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFalpha or TRAIL. However, concomitant repression of NF-kappaB and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNFalpha and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, to overcome cancers that are resistant to proapoptotic therapies.

SUBMITTER: Zhang X

PROVIDER: S-EPMC2715938 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.

Zhang Xiaoping X Huang Xu X Olumi Aria F AF

International journal of cancer 20090401 8

TNFalpha and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFalpha and TRAIL. We show that inhibition of NF-kappaB or ...[more]

PMID: 19123467

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Project description:BackgroundDuring the process of metastasis, cells are subjected to various apoptotic stimuli. Aberrant expression of apoptotic regulators often contribute to cell metastasis. Heat shock protein 27(HSP27) is confirmed as an apoptosis regulator, but its antiapoptotic mechanism in metastatic hepatocellular carcinoma (HCC) cells remains unclear.MethodsLevels of HSP27 protein and its phosphorylation in Hep3B, MHCC97L to MHCC97H cells with different metastatic potentials were determined by western blot analysis. MHCC97H cells were transfected with specific small interference RNA (siRNA) against HSP27. The in vitro migration and invasion potentials of cells were evaluated by Transwell assay. The apoptosis ratio of MHCC97H cells was analyzed by TUNEL staining and Flow Cytometry. Alteration of signal transduction pathway after HSP27 knockdown in MHCC97H cells was evaluated through a Human Q Series Signal Transduction in Cancer Gene Array analysis. Nuclear NF-kappaB contentration and endogenous IKK activity were demonstrated by ELISA assay. The association of IKKalpha, IKKbeta, IkappaBalpha with HSP27 and the association between IKKbeta and IKKalpha in MHCC97H cells were determined by co-immunoprecipitation assay followed by western blot analysis.ResultsHSP27 protein and its phosphorylation increased in parallel with enhanced metastatic potentials of HCC cells. siRNA-mediated HSP27 knockdown in MHCC97H significantly suppressed cells migration and invasion in vitro and induced cell apoptosis; the prominently altered signal transduction pathway was NF-kappaB pathway after HSP27 knockdown in MHCC97H cells. Furthermore, inhibition of HSP27 expression led to a significant decrease of nuclear NF-kappaB contentration and endogenous IKK activity. In addition, HSP27 was associated with IKKalpha, IKKbeta, IkappaBalpha in three HCC cells above. ELISA assay and western blot analysis also showed a decrease of the association between IKKbeta and IKKalpha, the association between phosphor-HSP27 and IKK complex, and an increase of total IkappaBalpha but reducing tendency of phosphor-IkappaBalpha when HSP27 expression was efficiently knocked down in MHCC97H cells.ConclusionAltogether, these findings revealed a possible effect of HSP27 on apoptosis in metastatic HCC cells, in which HSP27 may regulate NF-kB pathway activation.

Dataset Information

Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.

Publications

Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells.

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