MEKK3 expression correlates with nuclear factor κ B activity and with expression of antiapoptotic genes in serous ovarian carcinoma

Samanta, Abhishek; Huang, Helen J.; Le, Xiao Feng; Mao, Weiqun; Lu, Karen H.; Bast, Robert C.; Liao, Warren S.L.

doi:10.1002/cncr.24445

Cited by 27 publications

(27 citation statements)

References 117 publications

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“…Breast tumors that express high levels of MEKK3 have correspondingly high NF-κB binding activities, whereas tumors with low MEKK3 levels have low constitutive NF-κB binding activities, comparable with those of normal control breast tissues. This was consistent with reports by Samanta et al (21,22). Many types of cancer that have constitutively elevated NF-κB binding activity are resistant to apoptosis by conventional chemotherapies (25,26).…”

Section: Discussionsupporting

confidence: 92%

“…However, except for MEKK3, genetic studies have raised uncertainties regarding their involvement in the activation of NF-κB (20,21). Furthermore, studies have shown that overexpression of MEKK3 activates the NF-κB pathways (21,22). Recent studies showed that dysregulation of MEKK3 can affect NF-κB activation (23).…”

Section: Rnai Silencing Of the Mekk3 Gene Promotes Trailinduced Apoptmentioning

confidence: 99%

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RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

Guo

Liu²,

Liu³

et al. 2011

Oncol Rep

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Abstract. Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells or transformed cells, yet, it is relatively non-toxic to most normal cells. Consequently, TRAIL was thought to be a promising agent for cancer therapy. However, recent research reports revealed that many tumors are unresponsive to TRAIL treatment. Apoptotic agents were identified that when used in combination with TRAIL can sensitize tumor cells to TRAILmediated apoptosis. It was demonstrated that MEKK3-siRNA sensitized MCF-7 cells to TRAIL cytoxicity. In addition, we investigated the discrepancy of the expression of MEKK3 in breast cancers. It was concluded that elevated MEKK3 expression is found at high frequencies in breast cancer compared to normal breast tissue. Further experiments on the signal machinery showed that MEKK3-siRNA increased the sensitivity of MCF-7 cells to TRAIL by suppressing the transcription activity of NF-κB, and enhancing the caspaseprocessing to generate executive apoptotic signals. These findings indicate that down-regulation of MEKK3 by siRNA approaches will lead to successful treatment of human breast cancer with TRAIL.

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Section: Discussionsupporting

confidence: 92%

Section: Rnai Silencing Of the Mekk3 Gene Promotes Trailinduced Apoptmentioning

confidence: 99%

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

Guo

Liu²,

Liu³

et al. 2011

Oncol Rep

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“…In neoplasms, NF-κB has received specific attention for its role in oncogenesis (1)(2)(3)(4)(5). In addition, inducible chemoresistance is attributed to the activation of NF-κB, which in turn stimulates the transcription of anti-apoptotic genes enabling cells to overcome chemotherapy-induced apoptosis (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…One of the causes of chemoresistance is known to be upregulation of anti-apoptotic markers such as Bcl-2 and Bcl-xL, and this effect requires signaling through NF-κB (16,17). To determine whether the sensitization of SGC-7901 to chemotherapeutic agents was due to the downregulation of NF-κB and therefore, of Bcl-2 and Bcl-xL, we examined the levels of Bcl-2 and Bcl-xL.…”

Section: Chemotherapeutics Induce Apoptosis Jointly Using Curcumin Imentioning

confidence: 99%

Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor

Jing

Dai³

et al. 2011

Oncol Rep

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Abstract. Gastric cancer remains one of the major health problems worldwide. Chemotherapy is an important therapeutic modality for gastric cancer, but the success rate of this treatment is limited because of chemoresistance. The ubiquitously expressed transcription factor NF-κB has been suggested to be associated with chemoresistance of gastric cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance to chemotherapeutics are needed for the treatment of gastric cancer. Curcumin, a component of turmeric, is one such agent that has been shown to suppress NF-κB and increase the efficacy of chemotherapy. In this study, we investigated whether curcumin can reverse chemoresistance by downregulating NF-κB in human gastric cancer cells. SGC-7901 human gastric cancer cells was treated with chemotherapeutics (etoposide and doxorubicin) or by combined application of curcumin and chemotherapeutics. The viability of SGC-7901 cells was measured by MTT assay. Apoptosis of SGC-7901 cells was detected using the TUNEL and Annexin V/PI methods. The protein levels of NF-κB were analyzed by immunocytochemical staining. EMSA was used to confirm the increased nuclear translocation of RelA. The protein levels of p-IκBα, Bcl-2 and Bcl-xL were analyzed by Western blotting. The chemotherapeutics (etoposide and doxorubicin) suppressed the growth of SGC-7901 cells, in a time-dose-dependent manner. Use of curcumin in addition to these agents can suppress cell growth further (inhibitory rate: doxorubicin vs. doxorubicin + curcumin, 33% vs. 45%, p<0.05; etoposide vs. etoposide + curcumin, 35% vs. 48%, p<0.05). Furthermore, chemotherapeutics induced apoptosis of SGC-7901 cells and activated NF-κB. The combination of curcumin and chemotherapeutics induced apoptosis of SGC-7901 cells further, attenuated the activation of NF-κB, and reduced expression of the NF-κB-regulated anti-apoptotic gene products Bcl-2 and Bcl-xL. Curcumin potentiates the antitumor effects of chemotherapeutics in gastric cancer by suppressing NF-κB and NF-κB-regulated anti-apoptotic genes.

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“…AKT pathway activation induced by MAP17 expression may explain some of the properties described here. Under certain conditions, an increase in AKT activity may lead to a decrease in p38 phosphorylation; a decrease in AKT may lead to an increase in p38a phosphorylation, possibly through the release of the activity of p38 upstream kinases (most likely ASK1 and MEKK3) (Samanta et al, 2009). This relationship is further supported by the strong direct correlation between MAP17 levels and AKT phosphorylation and by the p38a dephosphorylation in breast tumors found in this work ( Figure 6) and by others (Huang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

p38α limits the contribution of MAP17 to cancer progression in breast tumors

et al. 2012

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MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in proteinexpressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38a activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38a. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS.

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MEKK3 expression correlates with nuclear factor κ B activity and with expression of antiapoptotic genes in serous ovarian carcinoma

Cited by 27 publications

References 117 publications

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor

p38α limits the contribution of MAP17 to cancer progression in breast tumors

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