Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells

Krüger, Katharina; Ziegler, Verena; Hartmann, Christina; Henninger, Christian; Thomale, Jürgen; Schupp, Nicole; Fritz, Gerhard

doi:10.1016/j.taap.2015.12.023

Cited by 20 publications

(13 citation statements)

References 74 publications

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“…Lovastatin and cilastatin, two well known clinical prescriptions to treat renal damage, also work as DDR inhibitors to protect cells from cisplatin-induced stress. 37,38 Consistently, we found that ELAs inhibited I/R-or H/R-induced activation of the DDR signaling pathway (Figures 2, 3, and 7). I/R injury triggers inflammatory responses and subsequently attracts neutrophil and macrophage infiltration into the tubulointerstitium, leading to kidney damage and development of fibrosis.…”

Section: Discussionsupporting

confidence: 78%

ELABELA and an ELABELA Fragment Protect against AKI

Chen

Wang

et al. 2017

JASN

115

133

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Renal ischemia-reperfusion (I/R) injury is the most common cause of AKI, which associates with high mortality and has no effective therapy. ELABELA (ELA) is a newly identified 32-residue hormone peptide highly expressed in adult kidney. To investigate whether ELA has protective effects on renal I/R injury, we administered the mature peptide (ELA32) or the 11-residue furin-cleaved fragment (ELA11) to hypoxia-reperfusion (H/R)-injured or adriamycin-treated renal tubular cells ELA32 and ELA11 significantly inhibited the elevation of the DNA damage response, apoptosis, and inflammation in H/R-injured renal tubular cells and suppressed adriamycin-induced DNA damage response. Similarly, overexpression of ELA32 or ELA11 significantly inhibited H/R-induced cell death, DNA damage response, and inflammation. Notably, treatment of mice with ELA32 or ELA11 but not an ELA11 mutant with a cysteine to alanine substitution at the N terminus (AE11C) inhibited I/R injury-induced renal fibrosis, inflammation, apoptosis, and the DNA damage response and markedly reduced the renal tubular lesions and renal dysfunction. Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI.

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Section: Discussionsupporting

confidence: 78%

ELABELA and an ELABELA Fragment Protect against AKI

Chen

Wang

et al. 2017

JASN

115

133

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“…There is a dose-dependent accumulation of DNA adducts in the presence of cisplatin. NRK-52E rat cells, in which 1,2-GpG-intrastrand crosslinks are not present ( Krüger et al, 2016 ), were incubated with cisplatin as a positive control. (B) Cisplatin induces egl-1 ectopic expression in somatic tissues during larval development.…”

Section: Resultsmentioning

confidence: 99%

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

García‐Rodríguez

Martínez-Fernández

Brena

et al. 2018

Disease Models &Amp; Mechanisms

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Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.

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“…Cisplatin is a DNA-damaging alkylating agent that triggers apoptotic cell death 5 . It is widely used in the treatment of various solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of GADD45A enhances chemosensitivity in melanoma

Liu

Jiang

Mao

et al. 2018

Sci Rep

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Melanoma is a malignant skin cancer with considerable drug resistance. Increased expression of DNA repair genes have been reported in melanoma, and this contributes to chemotherapy resistance. GADD45A is involved in DNA repair, cell cycle arrest and apoptosis in response to physiologic or environmental stresses. In this study, we investigated the role of GADD45A in chemotherapy response. Firstly, the mRNA expression of profiled DNA repair genes in cisplatin-treated melanoma cells was detected by RT2 profilerTM PCR array. We found the expression of GADD45A upregulated in a dose- and time- dependent manner. In addition, suppression of GADD45A sensitized melanoma cells to cisplatin and enhanced cisplatin-induced DNA damage. Flow cytometry revealed that downregulating GADD45A released cells from cisplatin-induced G2/M arrest and increased apoptosis. By using a MEK inhibitor, GADD45A was shown to be regulated by MAPK-ERK pathway following cisplatin treatment. Thus, the induction of GADD45A might play important roles in chemotherapy response in human melanoma cancer and could serve as a novel molecular target for melanoma therapy.

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Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells

Cited by 20 publications

References 74 publications

ELABELA and an ELABELA Fragment Protect against AKI

ELABELA and an ELABELA Fragment Protect against AKI

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

Down-regulation of GADD45A enhances chemosensitivity in melanoma

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