The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo

Hui, Kaiyuan; Yang, Yang; Shi, Kejian; Luo, Hui; Duan, Jing; An, Jiajia; Wu, Pa; Ci, Yali; Shi, Lei; Xu, Caimin

doi:10.1016/j.canlet.2014.08.009

Cited by 64 publications

(51 citation statements)

References 41 publications

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“…We first examined whether TES affected the MAPK signaling pathways, as these have previously been shown to play an important role in CRC [26, 27]. P38 phosphorylation levels were dramatically elevated in Lenti-TES cells compared with Lenti-NC cells, whereas extracellular signal-regulated kinase (ERK) and Jun N-terminal Kinase (JNK) were not significantly affected (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

TES inhibits colorectal cancer progression through activation of p38

Huang

Wang

et al. 2016

Oncotarget

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The human TESTIN (TES) gene has been identified as a candidate tumor suppressor based on its location at a common fragile site – a region where loss of heterozygosity has been detected in numerous types of tumors. To investigate its role in colorectal cancer (CRC), we examined TES protein levels in CRC tissue samples and cell lines. We observed that TES was markedly reduced in both CRC tissue and cell lines. Additionally, overexpression of TES significantly inhibited cell proliferation, migration, and invasion, while increasing cell apoptosis in colon cancer cells. By contrast, shRNA-mediated TES knockdown elicited the opposite effects. TES inhibited the progression of CRC by up-regulating pro-apoptotic proteins, down-regulating anti-apoptotic proteins, and simultaneously activating p38 mitogen-activated protein kinase (MAPK) signaling pathways. Collectively, these data indicate that TES functions as a necessary suppressor of CRC progression by activating p38-MAPK signaling pathways. This suggests that TES may have a potential application in CRC diagnosis and targeted gene therapy.

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Section: Resultsmentioning

confidence: 99%

TES inhibits colorectal cancer progression through activation of p38

Huang

Wang

et al. 2016

Oncotarget

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“…Moreover, it is also implicated in the initiation and progression of many human malignancies [28][29][30] . We observed that MEK2 was expressed highly in glioma cells, and its expression level increased as tumor grade advanced.…”

Section: Discussionmentioning

confidence: 99%

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Yao

Zhang

et al. 2015

Cell Mol Immunol

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Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

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“…These data suggested that RRM2 behaves as a critical effector which promotes CREB1 induced aggressiveness of CRC cells. In addition to increasing RRM2 expression, CREB1 also performs a role in inhibiting cell apoptosis by activating PKD1/CREB/Bcl-2 pathway in CRC [32]. Coincidently, RRM2 could also increase Bcl-2 protein stability in Head and Neck and Lung Cancers [33].…”

Section: Discussionmentioning

confidence: 99%

CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer

et al. 2016

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As the small subunit of Ribonucleotide reductase (RR), RRM2 displays a very important role in various critical cellular processes such as cell proliferation, DNA repair, and senescence, etc. Importantly, RRM2 functions like a tumor driver in most types of cancer but little is known about the regulatory mechanism of RRM2 in cancer development. In this study, we found that the cAMP responsive element binding protein 1 (CREB1) acted as a transcription factor of RRM2 gene in human colorectal cancer (CRC). CREB1 directly bound to the promoter of RRM2 gene and induced its transcriptional activation. Knockdown of CREB1 decreased the expression of RRM2 at both mRNA and protein levels. Moreover, knockdown of RRM2 attenuated CREB1-induced aggressive phenotypes of CRC cells in vitro and in vivo. Analysis of the data from TCGA database and clinical CRC specimens with immunohistochemical staining also demonstrated a strong correlation between the co-expression of CREB1 and RRM2. Decreased disease survivals were observed in CRC patients with high expression levels of CREB1 or RRM2. Our results indicate CREB1 as a critical transcription factor of RRM2 which promotes tumor aggressiveness, and imply a significant correlation between CREB1 and RRM2 in CRC specimens. These may provide the possibility that CREB1 and RRM2 could be used as biomarkers or targets for CRC diagnosis and treatment.

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The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo

Cited by 64 publications

References 41 publications

TES inhibits colorectal cancer progression through activation of p38

TES inhibits colorectal cancer progression through activation of p38

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer

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