Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Oh, You-Take; Yue, Ping; Zhou, Wei; Balko, Justin M.; Black, Esther P.; Owonikoko, Taofeek K.; Khuri, Fadlo R.; Sun, Shi‐Yong

doi:10.1074/jbc.m111.304006

Cited by 36 publications

(48 citation statements)

References 51 publications

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“…2). Vemurafenib reduced DR5 levels in SK-Mel19 cells, in agreement with previous studies [26](Supplemental Fig. 3A).…”

Section: Resultssupporting

confidence: 93%

“…We noted caspase 8 activation and PARP cleavage after long-term BRAF inhibition, preceded by up-regulation of FAS, but down-regulation of DR5, in agreement with other studies of DR5 regulation by activated RAS/RAF [26]. We noted suppression of FAS levels by expression of activated BRAF, which was relieved following treatment with vemurafenib.…”

Section: Discussionsupporting

confidence: 91%

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Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

et al. 2014

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Usp5 is a deubiquitinase (DUB) previously shown to regulate unanchored polyubiquitin (Ub) chains, p53 transcriptional activity and double-strand DNA repair. In BRAF mutant melanoma cells, Usp5 activity was suppressed by BRAF inhibitor (vemurafenib) in sensitive but not in acquired or intrinsically resistant cells. Usp5 knockdown overcame acquired vemurafenib resistance and sensitized BRAF and NRAS mutant melanoma cells to apoptosis initiated by MEK inhibitor, cytokines or DNA-damaging agents. Knockdown and overexpression studies demonstrated that Usp5 regulates p53 (and p73) levels and alters cell growth and cell cycle distribution associated with p21 induction. Usp5 also regulates the intrinsic apoptotic pathway by modulating p53-dependent FAS expression. A small molecule DUB inhibitor (EOAI3402143) phenocopied the FAS induction and apoptotic sensitization of Usp5 knockdown and fully blocked melanoma tumor growth in mice. Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule-mediated Usp5 inhibition. These results suggest that Usp5 inhibition can provide an alternate approach in recovery of diminished p53 (or p73) function in melanoma and can add to the targeted therapies already used in the treatment of melanoma.

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“…2). Vemurafenib reduced DR5 levels in SK-Mel19 cells, in agreement with previous studies [26](Supplemental Fig. 3A).…”

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

et al. 2014

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“…Several studies have suggested that PKCd activates ERK dependently of Raf (34). Recent studies have shown that Ras and B-Raf induce DR5 expression in an ERK/RSK2-dependent manner (35). So, it is necessary to investigate whether PKCd regulates ERK/RSK2 expression through activation of Ras and Raf.…”

Section: Discussionmentioning

confidence: 99%

PKCδ Regulates Death Receptor 5 Expression Induced by PS-341 through ATF4–ATF3/CHOP Axis in Human Lung Cancer Cells

2012

Molecular Cancer Therapeutics

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PS-341 (bortezomib), a proteasome inhibitor, has been approved for the treatment of multiple myeloma. Our previous work has shown that PS-341 induces death receptor 5 (DR5)-dependent apoptosis and enhances the TNF-related apoptosis-inducing ligand-induced apoptosis in human non-small cell lung cancer cells. However, the definite mechanism remains undefined. In the present study, we reveal that PKCd and RSK2 mediate PS-341-induced DR5 upregulation, involving coactivation of endoplasmic reticulum (ER) stress. We discovered that PS-341 activated ER stress through elevating the expression of BiP, p-eIF2a, IRE1a, ATF4, ATF3, and CCAAT/enhancer-binding protein homologous protein (CHOP). Further study showed that DR5 upregulation was dependent on ATF4, ATF3, and CHOP expression. Silencing either one of the ATF4, ATF3, and CHOP expression decreased DR5 upregulation and subsequent apoptosis. We determined that ATF4 regulated ATF3 and CHOP expression. Thereafter, ATF3 and CHOP formed a complex and regulated DR5 expression. In addition, we discovered that the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and RSK2 were elevated after PS-341 treatment and inhibition of their phosphorylation using MAP-ERK kinase 1/2 inhibitor decreased the DR5 level, indicating that ERK/RSK2 signaling is involved in DR5 upregulation. Furthermore, we detected the cleavage of PKCd, and the blockage of PKCd expression cut down DR5 upregulation and apoptosis. Importantly, knockdown of PKCd expression decreased the induction of ER stress and the phosphorylation of ERK1/2 and RSK2, suggesting that PKCd regulates DR5 expression through ERK/RSK2 signaling and ATF4-CHOP/ATF3 axis. Collectively, we show that PS-341 induces PKCd-dependent DR5 expression through activation of ERK/RSK2 and ER stress signaling pathway.

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“…A striking high expression of phosphorylated MEK and ERK was found in ALDH1 + NSCLC cells. Previous studies have shown that DR5 and DR4 expression is positively regulated by MEK/ERK signaling [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase 1 (ALDH1) Promotes the Toxicity of TRAIL in Non-Small Cell Lung Cancer Cells via Post-Transcriptional Regulation of MEK-1 Expression

Shen

Liu

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aim: Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-based therapies have been used in many human cancers. However, some tumors are resistant to TRAIL-induced cell death. Aldehyde dehydrogenase 1 (ALDH1) is a functional marker for identification of CSCs. Methods: In this study, we used the colony formation assay, AnnexinV/ PI double staining and PI staining to detect proliferation, apoptosis and cell cycle in ALDH1⁺ non-small cell lung cancer (NSCLC) cells with TRAIL treatment. In addition, we established xenograft mouse models to confirm the anti-tumor roles of TRAIL in vivo. Finally, gene array and western blot were used to detect the deeper mechanism of the susceptibility of ALDH1⁺ NSCLC cells to TRAIL. Results: We confirmed that TRAIL could inhibit proliferation, and induce apoptosis and G₁ arrest in ALDH1⁺ NSCLC cells. Correspondingly, TRAIL was associated with decreased tumor size and the favorable survival rate of ALDH1⁺ cells established xenograft mouse models. ALDH1 could increase the death receptors (DR) 4 and DR5 expression in ALDH1⁺ NSCLC cells via activating MEK/ERK signaling pathway. Conclusion: ALDH1 protein induced MEK-1 mRNA stability and promoted its translation via its 3’UTR.

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Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Cited by 36 publications

References 51 publications

Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

PKCδ Regulates Death Receptor 5 Expression Induced by PS-341 through ATF4–ATF3/CHOP Axis in Human Lung Cancer Cells

Aldehyde Dehydrogenase 1 (ALDH1) Promotes the Toxicity of TRAIL in Non-Small Cell Lung Cancer Cells via Post-Transcriptional Regulation of MEK-1 Expression

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