AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin-Like Growth Factor 1

Chen, Chong; Zhang, Qiuyang; Liu, Sen; Lambrechts, Mark J.; Qu, Yine; You, Zongbing

doi:10.3389/fonc.2014.00343

Cited by 10 publications

(22 citation statements)

References 55 publications

(55 reference statements)

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“…Of note, we observed that Akt was maintained in a hyperphosphorylated but catalytically inactive form in Ishikawa and MCF-7 cells after AZD5363 treatment. This phenomenon was also reported by other investigators 42, 43 . One possible mechanism is that Akt inhibitor sensitizes the Akt plekstrin homology (PH) domain binding to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which facilitates membrane localization of Akt and induces conformational change of Akt, making it more susceptible to kinase phosphorylation or less susceptible to phosphatase dephosphorylation 44 .…”

Section: Discussionsupporting

confidence: 90%

Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines

Yang¹,

Huang²,

Mei³

et al. 2017

Int J Gynecol Cancer

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Objective Estrogen is a well-known oncogenic driver in endometrial and breast cancers. Programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 have been shown to mediate immune evasion of the tumor cells. The purpose of the present study was to assess the effects of estrogen on PD-L1 and PD-L2 expression in endometrial and breast cancer cell lines. Methods 17β-estradiol (E2) -induced expression of PD-L1 and PD-L2 and possible signaling pathway were investigated in endometrial and breast cancer cells. Co-culture of T cells and cancer cells with E2 stimulation was performed to assess the functions of T cells. Results We found that 17β-estradiol (E2) increased expression of PD-L1, but not PD-L2 protein via activation of phosphoinositide 3-kinase (PI3K)/Akt pathway in Ishikawa and MCF-7 cells. PI3K and Akt inhibitors could block E2's effects. E2 did not increase PD-L1 mRNA transcription, but stabilized PD-L1 mRNA. E2's effects were only observed in estrogen receptor α (ERα) -positive Ishikawa and MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. Co-culture of Ishikawa or MCF-7 cells with T cells inhibited expression of interferon-γ and interleukin-2 and increased Bim expression in the presence of E2. Conclusion This study provides the first evidence that estrogen up-regulates PD-L1 protein expression in ERα-positive endometrial and breast cancer cells to suppress immune functions of T cells in the tumor microenvironment, demonstrating a new mechanism of how estrogen drives cancer progression.

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Section: Discussionsupporting

confidence: 90%

Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines

Yang¹,

Huang²,

Mei³

et al. 2017

Int J Gynecol Cancer

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“…We believe this mechanism may also be true for the enhanced expression of VCAM-1 in HUVECs treated with IL-17 and insulin/IGF1. IL-17 alone did not dramatically increase VCAM-1 expression to enhance adhesion because GSK3 negatively inhibits IL-17 signaling as demonstrated by previous studies [17,33,34]. In the presence of IGF1 or insulin, GSK3 function is inhibited by PI3K/Akt activated by IGF1 or insulin [17,33], thus VCAM-1 expression and subsequent adhesion are enhanced by IL-17.…”

Section: Discussionmentioning

confidence: 62%

“…IL-17 alone did not dramatically increase VCAM-1 expression to enhance adhesion because GSK3 negatively inhibits IL-17 signaling as demonstrated by previous studies [17,33,34]. In the presence of IGF1 or insulin, GSK3 function is inhibited by PI3K/Akt activated by IGF1 or insulin [17,33], thus VCAM-1 expression and subsequent adhesion are enhanced by IL-17. We have shown that the synergy between IL-17 and insulin/IGF1 can be blocked by melatonin that inhibits Akt [17] or by a new pan-Akt inhibitor AZD5363 [33].…”

Section: Discussionmentioning

confidence: 62%

“…Insulin and IGF1 can activate PI3K/Akt to phosphorylate GSK3B at serine 9 and inhibit GSK3B activity, and consequently increase C/EBPβ function to enhance IL-17-induced gene expression. Recently, we have demonstrated that insulin and IGF1 can also activate PI3K/Akt to phosphorylate GSK3A at serine 21 and inhibit GSK3A activity, and consequently enhance IL-17-induced gene expression [33]. We believe this mechanism may also be true for the enhanced expression of VCAM-1 in HUVECs treated with IL-17 and insulin/IGF1.…”

Section: Discussionmentioning

confidence: 96%

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IL‐17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44‐VCAM‐1 interaction

et al. 2015

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BACKGROUND Extravasation is a critical step in cancer metastasis, in which adhesion of intravascular cancer cells to the vascular endothelial cells is controlled by cell surface adhesion molecules. The role of interleukin-17 (IL-17), insulin, and insulin-like growth factor 1 (IGF1) in adhesion of prostate cancer cells to the vascular endothelial cells is unknown, which is the subject of the present study. METHODS Human umbilical vein endothelial cells (HUVECs) and human prostate cancer cell lines (PC-3, DU-145, LNCaP, and C4-2B) were analyzed for expression of vascular cell adhesion molecule 1 (VCAM-1), integrins, and cluster of differentiation 44 (CD44) using flow cytometry and Western blot analysis. The effects of IL-17, insulin and IGF1 on VCAM-1 expression and adhesion of prostate cancer cells to HUVECs were examined. The interaction of VCAM-1 and CD44 was assessed using immunoprecipitation assays. RESULTS Insulin and IGF1 acted with IL-17 to increase VCAM-1 expression in HUVECs. PC-3, DU-145, LNCaP, and C4-2B cells expressed β1 integrin but not α4 integrin. CD44 was expressed by PC-3 and DU-145 cells but not by LNCaP or C4-2B cells. When HUVECs were treated with IL-17, insulin or IGF1, particularly with a combination of IL-17 and insulin (or IGF1), adhesion of PC-3 and DU-145 cells to HUVECs was significantly increased. In contrast, adhesion of LNCaP and C4-2B cells to HUVECs was not affected by treatment of HUVECs with IL-17 and/or insulin/IGF1. CD44 expressed in PC-3 cells physically bound to VCAM-1 expressed in HUVECs. CONCLUSIONS CD44-VCAM-1 interaction mediates the adhesion between prostate cancer cells and HUVECs. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through increasing VCAM-1 expression in the vascular endothelial cells. These findings suggest that IL-17 may act with insulin/IGF1 to promote prostate cancer metastasis.

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“…This finding is consistent with the finding that IL-17 and/or TNF-α activated NF-κB signaling as early as 5 minutes upon the treatment. AZD5363 is a pan-AKT inhibitor [29]. AZD5363 diminished PD-L1 protein expression induced by IL-17 and/or TNF-α in LNCaP cells, whereas it only diminished PD-L1 protein expression induced by IL-17 in HCT116 cells.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

et al. 2017

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Programmed cell death protein 1 (PD-1) acts on PD-1 ligands (PD-L1 and PD-L2) to suppress activation of cytotoxic T lymphocytes. Interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) are co-expressed by T helper 17 (TH17) cells in many tumors. The purpose of this study was to test if IL-17 and TNF-α may synergistically induce PD-L1 expression in human prostate cancer LNCaP and human colon cancer HCT116 cell lines. We found that IL-17 did not induce PD-L1 mRNA expression, but up-regulated PD-L1 protein expression in HCT116 and LNCaP cells. TNF-α induced PD-L1 mRNA and protein expression in both cell lines. Neither IL-17 nor TNF-α induced PD-L2 mRNA or protein expression. IL-17 and TNF-α acted individually rather than cooperatively in induction of PD-L1 expression. IL-17 and/or TNF-α activated AKT, nuclear factor-κB (NF-κB), and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways in HCT116 cells, whereas only NF-κB signaling was activated in LNCaP cells. NF-κB inhibitor could diminish PD-L1 protein expression induced by IL-17 and/or TNF-α in both HCT116 and LNCaP cell lines. ERK1/2 inhibitor could also reduce PD-L1 protein expression induced by IL-17 and/or TNF-α in HCT116 cells, while AKT inhibitor could abolish PD-L1 protein expression induced by IL-17 and/or TNF-α in LNCaP cells. These results suggest that IL-17 and TNF-α act individually rather than cooperatively through activation of NF-κB and ERK1/2 signaling to up-regulate PD-L1 expression in HCT116 cells, while the two inflammatory cytokines act through activation of NF-κB signaling, in the presence of AKT activity, to up-regulate PD-L1 expression in LNCaP cells.

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AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin-Like Growth Factor 1

Cited by 10 publications

References 55 publications

Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines

Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines

IL‐17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44‐VCAM‐1 interaction

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

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