Downregulation of DEPTOR inhibits the proliferation, migration, and survival of osteosarcoma through PI3K/Akt/mTOR pathway

Hu, Binwu; Lv, Xiao; Gao, Feng; Chen, Songfeng; Wang, Shangyu; Xia, Qing; Liu, Jianxiang; Wang, Baichuan; Shao, Zengwu

doi:10.2147/ott.s143518

Cited by 24 publications

(20 citation statements)

References 46 publications

(62 reference statements)

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“…Notably, in 2013, Zhang and collaborators have demonstrated that, in multiple myeloma cells, a reduction of 50% in DEPTOR mRNA lead to a similar decrease at the protein level and to changes in the profile of downstream elements of mTOR pathway (as in the phosphorylation of 4EBP1 and Akt), as well as a reduction of cell proliferation 31,32 . A similar result was observed in studies with multiple myeloma 28 and osteosarcoma 33 cells, where higher levels of DEPTOR knockdown were obtained. On the other hand, DEPTOR influence on the cell cycle and proliferation varies in different cell types.…”

Section: Discussionsupporting

confidence: 86%

Cell cycle genes are downregulated after adipogenic triggering in human adipose tissue-derived stem cells by regulation of mRNA abundance

Marcon

Shigunov

Spangenberg

et al. 2019

Sci Rep

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The adipogenic process is characterized by the expression of adipocyte differentiation markers that lead to changes in cell metabolism and to the accumulation of lipid droplets. Moreover, during early adipogenesis, cells undergo a strong downregulation of translational activity with a decrease in cell size, proliferation and migration. In the present study, we identified that after 24 hours of adipogenic induction, human adipose tissue-derived stem cells (hASCs) undergo a G1-cell cycle arrest consistent with reduced proliferation, and this effect was correlated with a shift in polysome profile with an enrichment of the monosomal fraction and a reduction of the polysomal fraction. Polysome profiling analysis also revealed that this change in the monosomal/polysomal ratio was related to a strong downregulation of cell cycle and proliferation genes, such as cyclins and cyclin-dependent kinases (CDKs). Comparing total and polysome-associated mRNA sequencing, we also observed that this downregulation was mostly due to a reduction of cell cycle and proliferation transcripts via control of total mRNA abundance, rather than by translational control.

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Section: Discussionsupporting

confidence: 86%

Cell cycle genes are downregulated after adipogenic triggering in human adipose tissue-derived stem cells by regulation of mRNA abundance

Marcon

Shigunov

Spangenberg

et al. 2019

Sci Rep

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“…A number of studies have shown that the PI3K/AKT pathway is involved in osteosarcoma (46)(47)(48). mTOR, one of the PI3K family members, is important in the regulation of cell cycle, growth and development; the PI3K/AKT/mTOR signaling pathway is reported to be involved in the proliferation, migration and survival of osteosarcoma (49). The results of the present study showed that, in the U2OS and MG63 cell lines, the expression of TRIM2 was inhibited, the protein level of phosphorylated-AKT was decreased, and the level of AKT was unchanged, which indicated that the AKT signaling was implicated in the regulatory pathway of TRIM2.…”

Section: Discussionmentioning

confidence: 99%

TRIM2 regulates the development and metastasis of tumorous cells of osteosarcoma

Qin

Zhao

et al. 2018

Int J Oncol

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The present study aimed to investigate candidate genes involved in the development and metastasis of osteosarcoma. Candidate genes were screened preliminarily from the Gene Expression Omnibus database and then validated using actual tumor tissues collected from patients with osteosarcoma. The cells were prepared and transfected with specific gene-targeted small interfering RNA followed by an MTS assay for cell viability detection and Transwell assays for cell migration and invasion capacity detection. The cell apoptosis was determined by flow cytometry and the protein level of the genes was detected by western blot analysis. An in vivo nude model was used and injected with cells to detect the functions of the genes. Transcriptome sequencing was performed to verify the regulation network, followed by reverse transcription-quantitative polymerase chain reaction and western blot analyses for validation. Increased tripartite motif-containing protein 2 (TRIM2) was detected in the osteosarcoma tumor tissues compared with normal tissues. The inhibition of TRIM2 induced lower cell viability and cell invasion capacity, and increased the rate of cell apoptosis. Decreased TRIM2 also inhibited the development and metastasis of osteosarcoma in the nude mouse models. The transcriptome sequencing revealed that the regulation of TRIM2 may be correlated with genes, Sirtuin 4, DNA damage inducible transcript 3, cAMP responsive element binding protein 5, G protein-coupled receptor 65 (GPR65) and ADP-ribosyltransferase 5. Western blot analysis indicated that TRIM2 regulated the development and metastasis of osteosarcoma via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Therefore, TRIM2 performs important functions in regulating the development and metastasis of osteosarcoma.

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“…For example, in many cancer cells, deptor level is significantly reduced and consequently both mTORC1 and mTORC2 activities are increased [ 17 , 64 , 65 ]. On the other hand, in multiple myelomas, hepatocellular carcinoma, thyroid carcinoma and osteosarcomas, increased deptor expression suppresses mTORC1 activity, which increases the phosphorylation of Akt by relieving the negative feed-back loop on PI 3 kinase/IRS-1 [ 17 , 66 – 68 ]. However, the role of deptor in podocytes does not align with its function found in these cancers.…”

Section: Discussionmentioning

confidence: 99%

Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression

et al. 2018

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TGFβ promotes podocyte hypertrophy and expression of matrix proteins in fibrotic kidney diseases such as diabetic nephropathy. Both mTORC1 and mTORC2 are hyperactive in response to TGFβ in various renal diseases. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. We identified that deptor downregulation by TGFβ maintains hyperactive mTOR in podocytes. To unravel the mechanism, we found that TGFβ -initiated noncanonical signaling controls deptor inhibition. Pharmacological inhibitor of PI 3 kinase, Ly 294002 and pan Akt kinase inhibitor MK 2206 prevented the TGFβ induced downregulation of deptor, resulting in suppression of both mTORC1 and mTORC2 activities. However, specific isoform of Akt involved in this process is not known. We identified Akt2 as predominant isoform expressed in kidney cortex, glomeruli and podocytes. TGFβ time-dependently increased the activating phosphorylation of Akt2. Expression of dominant negative PI 3 kinase and its signaling inhibitor PTEN blocked Akt2 phosphorylation by TGFβ. Inhibition of Akt2 using a phospho-deficient mutant that inactivates its kinase activity, as well as siRNA against the kinase markedly diminished TGFβ -mediated deptor suppression, its association with mTOR and activation of mTORC1 and mTORC2. Importantly, inhibition of Akt2 blocked TGFβ -induced podocyte hypertrophy and expression of the matrix protein fibronectin. This inhibition was reversed by the downregulation of deptor. Interestingly, we detected increased phosphorylation of Akt2 concomitant with TGFβ expression in the kidneys of diabetic rats. Thus, our data identify previously unrecognized Akt2 kinase as a driver of TGFβ induced deptor downregulation and sustained mTORC1 and mTORC2 activation. Furthermore, we provide the first evidence that deptor downstream of Akt2 contributes to podocyte hypertrophy and matrix protein expression found in glomerulosclerosis in different renal diseases.

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Downregulation of DEPTOR inhibits the proliferation, migration, and survival of osteosarcoma through PI3K/Akt/mTOR pathway

Cited by 24 publications

References 46 publications

Cell cycle genes are downregulated after adipogenic triggering in human adipose tissue-derived stem cells by regulation of mRNA abundance

Cell cycle genes are downregulated after adipogenic triggering in human adipose tissue-derived stem cells by regulation of mRNA abundance

TRIM2 regulates the development and metastasis of tumorous cells of osteosarcoma

Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression

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