Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling

Akool, El-Sayed; Gauer, Stefan; Osman, Bashier; Doller, Anke; Schulz, Sebastian; Geiger, Helmut; Pfeilschifter, Josef; Eberhardt, W.

doi:10.1016/j.bcp.2011.11.001

Cited by 35 publications

(28 citation statements)

References 48 publications

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“…2C and Fig. 6A), which is consistent with previous findings [29]. In addition, the inhibition of ERK activation by 8-MOP happens very quickly, in which 8-MOP significantly suppresses ERK phosphorylation after the incubation lasting for 1 min (Fig.…”

Section: Discussionsupporting

confidence: 81%

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Yang

Xiong

Luo

et al. 2015

Cell Physiol Biochem

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Background/Aims: 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, induces apoptosis when used alone. On this basis, the present study was designed to explore the effects and mechanisms of 8-MOP-induced apoptosis in human hepatocellular carcinoma HepG2 cells, independent of its photoactivation. Methods: We analyzed the cell viability with MTT assay. Flow cytometry was used to examine the apoptosis rate, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation after specific staining. The expression and location of apoptosis-associated protein as well as the activation status of cell signaling pathway were determined by Western blot analysis. Results: 8-MOP significantly decreased cell viability and induced cell apoptosis through mitochondrial apoptotic pathway, as demonstrated by increased Bax/Bcl-2 ratio, collapsed MMP, and induced cytochrome c release (Cyt c) and apoptosis-inducing factor (AIF) transposition. ROS generation was significantly increased by 8-MOP and the eradication of ROS significantly abolished 8-MOP-induced apoptosis. In addition, the activation of ERK1/2 was drastically decreased by 8-MOP as ERK inhibitor PD98059, indicating a role of ERK1/2 signaling pathway in 8-MOP-induced cell apoptosis. Conclusion: 8-MOP induces intrinsic apoptosis by increasing ROS generation and inhibiting ERK1/2 pathway in HepG2 cells. The findings are important in substantiating the anti-tumor role of 8-MOP in cancer therapy.

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Section: Discussionsupporting

confidence: 81%

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Yang

Xiong

Luo

et al. 2015

Cell Physiol Biochem

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“…Similar results were also found in an Ang II-induced glomerular mesangial cell (GMC) proliferation study, and the results revealed that p-ERK1/2 acted as an upstream signaling molecule for TRPC6 [29]. Another study showed that FK506 could activate the ERK1/2 signaling cascade in rat renal mesangial cells [30]. Previous studies have also focused on the relationships of TRPC channels and ERK1/2, though which the upstream signaling molecule remains controversial [18, 21, 22, 29, 31-35].…”

Section: Introductionsupporting

confidence: 64%

Therapeutic Effects of FK506 on IgA Nephropathy Rat

Wei

Jia

et al. 2017

Kidney Blood Press Res

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Background/Aims: FK506 is an immunosuppressive drug and a calcineurin inhibitor that has been widely used in kidney disease in recent years. FK506 shows a wide range of biological and pharmaceutical effects; however, the mechanism of its anti- proliferative effect has not been well elucidated. An IgA nephropathy (IgAN) model was used to generate a mesangial cell proliferation model. This study aims to examine the effect of FK506 on IgAN rats and the underlying mechanisms. Methods: Hematuria, proteinuria and renal function were measured. To observe the pathological conditions, we performed HE (hematoxylin - eosin) and PAS (periodic acid - schiff) staining. Transcription and protein expression levels were detected by qRT - PCR (quantitative real-time polymerase chain reaction) and Wb (western blotting). The location and semi-quantitative expression levels of TRPCs, CaN (Calcineurin) and α-SMA were examined by IHC (Immunohistochemical staining). Results: We found that FK506 could improve hematuria, proteinuria and renal function, especially in the HF (high-dose FK506) groups. Renal pathological changes were ameliorated in the treatment groups. FK506 could significantly decrease TRPCs, CaN, phosphorylation of ERK1/2 and α-SMA expression. Conclusion: Taken together, these results suggest that the therapeutic effect of FK506 on IgAN might be partially associated with the down-regulated expression of TRPC channels, CaN and phosphorylation of ERK1/2.

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“…Release of mitochondrial ROS can stimulate mitogenic pathways in tumor and stromal cells (22,34). Staining of CsA-treated LuEC with the mitochondrial superoxide marker Mitosox (8,20) shows increased fluorescence compared to vehicle treated cells, (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CsA is known to bind to cyclophilin D, a mitochondrial localized cyclophilin and part of the mitochondria permeability transition pore (MPTP). During calcium and oxidative stress, CsA limits superoxide release by inhibiting high-conductive irreversible MPTP opening (30), but has also been shown in other situations to increase mitochondrial ROS levels (8,33,34). Under basal, or non-apoptotic conditions, the MPTP has also been found to open briefly in transient “superoxide flashes” (35,47), or ‘low-conductive’ openings which do not result in mitochondrial swelling or massive release of mitochondrial contents.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A Promotes Tumor Angiogenesis in a Calcineurin-Independent Manner by Increasing Mitochondrial Reactive Oxygen Species

Zhou

Ryeom

2014

Molecular Cancer Research

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The widely used immunosuppressant cyclosporin A (CsA), a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term CsA treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, prolonged treatment with CsA promoted tumor growth and angiogenesis. The addition of CsA to endothelial cells in vitro increased proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species (ROS). Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings suggest that CsA affects endothelial cells in a calcineurin-independent manner to potentiate tumor growth by promoting tumor angiogenesis through increasing mitochondrial ROS production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants would inhibit the tumor promoting effects of CsA.

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Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling

Cited by 35 publications

References 48 publications

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Therapeutic Effects of FK506 on IgA Nephropathy Rat

Cyclosporin A Promotes Tumor Angiogenesis in a Calcineurin-Independent Manner by Increasing Mitochondrial Reactive Oxygen Species

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