PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts

Bluwstein, Andrej; Kumar, Nitin; Léger, Karolin; Traenkle, Jens; Oostrum, Jan van; Rehrauer, Hubert; Baudis, Michael; Hottiger, Michael O.

doi:10.1038/cddis.2013.15

Cited by 46 publications

(33 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CREB phosphorylation is mainly controlled by protein kinase A (PKA) and calcium‐dependent protein kinase (PKC), casein kinase (CK II), MAPK, AKT pathway . Next, we further confirmed the effect of EGFR downstream MEK, PI3K pathway on p‐CREB level in cell nucleus by using the EGFR and its downstream inhibitors.…”

Section: Resultsmentioning

confidence: 69%

Synergistic combination of DT‐13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC‐823 cells via NM IIA/EGFR/HK II axis

Wei²,

Gao

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

DT‐13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT‐13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis‐related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non‐muscle myosin IIA (NM IIA)‐induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT‐13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (‐)002Dblebbistatin or MYH‐9 shRNA, the synergistic inhibition effect of DT‐13 and TPT on aerobic glycolysis was eliminated in BGC‐823 cells. Immunohistochemical analysis revealed selective up‐regulation of NM IIA while specific down‐regulation of p‐CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.

show abstract

Section: Resultsmentioning

confidence: 69%

Synergistic combination of DT‐13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC‐823 cells via NM IIA/EGFR/HK II axis

Wei²,

Gao

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…In general, increase of p21 (Cip1/Waf1) suppresses broad range of cyclin/CDK complexes, which leads to G1, G2 and S-phase arrest. Thus, p21 (Cip1/Waf1) represses stemness through the regulation of the cell cycle 21 , and is a well-characterized radiation marker that is activated by PKC 11,22 . In keratinocytes, p21 (Cip1/Waf1) is increased by calcium-induced keratinocyte differentiation 23 .…”

Section: Resultsmentioning

confidence: 99%

170 Single low-dose radiation induced regulation of keratinocyte differentiation in calcium-induced HaCaT cells

Hahn

Lee

Choi

et al. 2017

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Background: We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective: We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods: To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Results: Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. Conclusion: These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. (Ann Dermatol 28(4) 433∼

show abstract

“…The finding of reduced levels of several pPKC isoforms in FKBP51-depleted IR sensitive melanoma is consistent with the notion that PKC is one of the earliest responders to IR. PKC has been shown to be involved in radiation resistance in different cellular systems [32,33], and its inhibition increases the cell killing by IR [10][11][12]. Enzastaurin, or LY317615, is a synthetic bisindolylmaleimide drug developed by Eli Lilly.…”

Section: Discussionmentioning

confidence: 99%

A Role for Proteomics in Identifying Targets for Radiosensitizing Strategies in Melanoma: The FKBP51 Paradigm

Dilhas¹,

Pacelli²,

Martinelli³

et al. 2014

J Proteomics Bioinform Vol.

View full text Add to dashboard Cite

The treatment of metastatic melanoma is challenging and in the vast majority of cases unsuccessful. Melanoma cells are resistant to most standard therapeutics. We have recently demonstrated that FKBP51 regulates melanoma response to ionizing radiation (IR). To find out molecular targets for radiosensitizing strategies to apply in this neoplasm, we investigated the changes of protein profiles in irradiated melanoma depleted or not of FKBP51, by protein microarray approach. Among the multiple molecules that were found modulated in our cell model, the decrease of several pPKC isoforms in the FKBP51-depleted (IR-sensitive) melanoma appeared to us particularly interesting, because PKC is involved in radiation response. Therefore, PKC was chosen for further investigation. After validating by western blot proteomics results, we found that targeting PKC, with the pan PKC inhibitor LY317615 or enzastaurin, significantly enhanced IR-induced cell death. Most interestingly, enzastaurin combined with IR appeared to be effective in eliminating a subset of melanoma cells expressing a stemness marker. Our study highlighted a role for proteomics in finding useful targets to overcome melanoma resistance, and suggested a combination treatment, which deserves to be investigated in a clinical setting.

show abstract

PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts

Cited by 46 publications

References 56 publications

Synergistic combination of DT‐13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC‐823 cells via NM IIA/EGFR/HK II axis

Synergistic combination of DT‐13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC‐823 cells via NM IIA/EGFR/HK II axis

170 Single low-dose radiation induced regulation of keratinocyte differentiation in calcium-induced HaCaT cells

A Role for Proteomics in Identifying Targets for Radiosensitizing Strategies in Melanoma: The FKBP51 Paradigm

Contact Info

Product

Resources

About