IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

Ma, Xiumei; Bai, Yongrui

doi:10.3892/mmr.2012.1110

Cited by 44 publications

(38 citation statements)

References 43 publications

(43 reference statements)

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“…This suggests that IGF-1 stimulates the PI3K/Akt signaling pathway, and is consistent with the work of others [44]. It is very likely that inhibition of IGF-1 leads to down-regulation in expression of the MHC-1 antigen processing [45].…”

Section: Discussion and Summarysupporting

confidence: 90%

Rescue of MHC-1 Antigen Processing Machinery by Down-Regulation in Expression of IGF-1 in Human Glioblastoma Cells

et al. 2013

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Escape from immune recognition has been hypothesized to be a factor in carcinogenesis. It may be mediated for many cancers through down-regulation in the MHC class 1 antigen processing and presentation pathway. TAP-1, TAP-2, tightly linked to LMP-2 and LMP-7 are multiple components of the endogenous, antigen presentation pathway machinery. We addressed the question of alterations in this pathway in human Glioblastoma (HGB) and of its relationship to modulation in expression of IGF-1 that is highly expressed in this cancer. Deficiencies in expression of TAP-1 were demonstrated by RT-PCR and/or by immuno-flow cytometry in the HGB cell line T98G obtained from ATCC, and in 3 of 4 human cell lines established from patients with Glioblastoma Multiforme. Deficiencies in expression of TAP-2 were observed in 3 of 4, deficiencies in expression of LMP-2 in 4 of 4 and deficiencies in LMP-7 in 3 of 4 HGB cell lines examined by RT-PCR and Western blot. Following down-regulation of IGF-1 by transfection with the pAnti IGF-1 vector that expresses IGF-1 RNA in antisense orientation, or by the exogenous addition of IGF-1 receptor monoclonal antibody to cell culture media, the deficiencies in components of the MHC-1 antigen presentation pathway were up-regulated and/or rescued in all HGB cell lines tested. Moreover, this up-regulation in expression was aborted by addition of 100 ng/ml of IGF-1 to the culture media. Unlike in the case of IFN-γ, the restoration of TAP-1 and LMP-2 by down-regulation of IGF-1 in Glioblastoma cells was not correlated to the tyrosine phosphorylation of STAT 1. In summary, the simultaneous reversion in expression of the multiple constituents of MHC-1 antigen processing path and up-regulation in expression of MHC-1 occurring with down-regulation in IGF-1 may have a role in reinforcement of immunity against tumor antigen(s) in some animal cancers and in humans with Glioblastoma Multiforme.

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Section: Discussion and Summarysupporting

confidence: 90%

Rescue of MHC-1 Antigen Processing Machinery by Down-Regulation in Expression of IGF-1 in Human Glioblastoma Cells

et al. 2013

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“…PI3K/AKT and ERK1/2 is believed to act downstream of sCLU [16,17,34,35,36]. In this study, DDP could up-regulate the expression of sCLU, which is correlated with the activation of pAKT and pERK1/2.…”

Section: Discussionmentioning

confidence: 56%

“…We therefore suggested ERK1/2 signalling is regulated by clusterin. Many studies in literature have reported that AKT pathway may also regulated by clusterin in cancers including lung cancer [17,35,36]. …”

Section: Introductionmentioning

confidence: 99%

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Zhang¹,

Zhang²,

Liu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). Methods: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549^DDPin vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. Results: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549^DDP and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549^DDP cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204}, and vice versa. Inhibition of pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204} was sufficient to induce significant recover y in chemosensitivity to DDP in A549^DDP in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. Conclusions: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy.

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“…However, Bcl-2 suppression is a p53-independent effect, such that knockdown of p53 only minimally suppressed cell death, but a pan-caspase inhibitor completely avoided cell death. Another mechanism involved in sCLU prosurvival activity is the upregulation of the phosphatidylinositol 3- kinase (PI3K)/protein kinase B (AKT) pathway15 and insulin-like growth factor (IGF)-1 activates the PI3K/AKT pathway through upregulation of sCLU 16…”

Section: Clusterin Actionsmentioning

confidence: 99%

Clusterin: a key player in cancer chemoresistance and its inhibition

Koltai¹

2014

OTT

136

104

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Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others. Its overexpression should be considered as a nonspecific cellular response to a wide variety of tissue insults like cytotoxic chemotherapy, radiation, excess of free oxygen radicals, androgen or estrogen deprivation, etc. A review of the recent literature strongly suggests potential roles for custirsen in particular, and proapoptosis treatments in general, as novel modalities in cancer management. Inhibition of clusterin is known to increase the cytotoxic effects of chemotherapeutic agents, and custirsen, a second-generation antisense oligonucleotide that blocks clusterin, is being tested in a Phase III clinical trial after successful results were achieved in Phase II studies. A major issue in cancer evolution that remains unanswered is whether clusterin represents a driving force of tumorigenesis or a late phenomenon after chemotherapy. This review presents preclinical data that encourages trials in various types of cancer other than advanced castration-resistance prostate cancer and discusses briefly the appropriate timing for clusterin inhibition in the clinical context.

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IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

Cited by 44 publications

References 43 publications

Rescue of MHC-1 Antigen Processing Machinery by Down-Regulation in Expression of IGF-1 in Human Glioblastoma Cells

Rescue of MHC-1 Antigen Processing Machinery by Down-Regulation in Expression of IGF-1 in Human Glioblastoma Cells

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Clusterin: a key player in cancer chemoresistance and its inhibition

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