Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation

Chen, Lan; Li, Tianyu; Tu, Yunhua; Rong, Dongyun; Cao, Yu

doi:10.3892/or.2015.4442

Cited by 11 publications

(8 citation statements)

References 33 publications

(43 reference statements)

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“…DEPTOR is an mTORC1 inhibitor [30, 31], which is closely related to cell proliferation, inflammation, obesity, and cancer [32, 33] and directly connected with cardiovascular disease [34, 35]. One study reported that DEPTOR regulates vascular EC activation and contributes to proinflammatory and angiogenic responses in vitro [18].…”

Section: Discussionmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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Section: Discussionmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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“…DEPTOR is an inhibitor of both mTORC1 and mTORC2. mTOR activation can phosphorylate DEPTOR and promote its recognition by SCF β-TrCP ubiquitin ligase, targeting DEPTOR for polyubiquitination and proteolytic degradation [ 51 , 52 ]. In tumors with isocitrate dehydrogenase1/2 (IDH1/2) mutations, oncometabolite 2-hydroxyglutarate indirectly promotes DEPTOR polyubiquitination by SCF β-TrCP , thus activating mTOR [ 51 ].…”

Section: Ubiquitination and Metabolic Signaling Pathwaysmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

256

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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“…Consistent with these findings, MLN4924 indeed further inactivated mTORC1 and downregulated NF-κB in HCC cells compared to sorafenib alone. This was mediated by the increase in Deptor and IκBɑ, known substrates of SCF-βTrCP, as demonstrated in melanoma and HCC cancer cell lines (47,48). However, we did not observe an increase in Noxa, a known substrate of CRL5, in the MLN4924 only treatment group in HCC cells.…”

Section: Discussionmentioning

confidence: 83%

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

et al. 2019

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Sorafenib remains the standard care for patients with hepatocellular carcinoma (HCC) even though it has low antitumor efficacy. Protein neddylation is abnormally activated in many types of human cancer. However, whether dysregulation of neddylation is involved in HCC progression and whether targeting neddylation sensitizes HCC cells to sorafenib need to be ascertained. In the present study, it was demonstrated that high expression of neddylation components, neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and NEDD8-activating enzyme 1 (NAE1), were associated with poor survival of patients with HCC. Inhibition of neddylation by MLN4924, a small-molecule inhibitor of NAE1, significantly inhibited HCC growth, reduced clonogenic survival, increased apoptosis, and decreased migration capacity. Sorafenib alone exhibited minimal anticancer efficacy. However, a combination of sorafenib with MLN4924 at a low concentration significantly enhanced the inhibition of cell proliferation and migration as well as the induction of apoptosis induced by sorafenib. In vivo HCC xenograft mouse models also showed that MLN4924 increased the antitumor efficacy of sorafenib. Mechanistically, MLN4924 enhanced the antitumor activity of sorafenib in HCC cells via upregulation of cullin-RING E3 ubiquitin ligase (CRL)/Skp1-Cullin1-F box (SCF) E3 ubiquitin ligase substrates p21, p27, Deptor and IκBɑ. Taken together, these findings suggest that combination therapy of MLN4924 with sorafenib appears to present an additive effect with a maximal in the treatment of HCC.

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Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation

Cited by 11 publications

References 33 publications

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

The role of ubiquitination and deubiquitination in cancer metabolism

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

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