Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

Hußner, Janine; Ameling, Sabine; Hammer, Elke; Herzog, Susann; Steil, Leif; Schwebe, Matthias; Niessen, Juliane; Schroeder, Henry Ws; Kroemer, Heyo K.; Völker, Uwe; Bien, Sandra

doi:10.1124/mol.111.075994

Cited by 25 publications

(18 citation statements)

References 30 publications

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“…An independent pairwise comparison of the DOX vs. DOXTOX at baseline and DOX vs. DOXTOX at 1 µM again identified RELA, NFKB1 , and RARA (retinoic acid receptor alpha) with significantly ( P < 1.8 × 10 −4 ) altered target gene expression, and signal transducer and activator of transcription 3 as significant signaling pathway, which were previously described 39, 40 (Supplementary Table 5). In addition, we identified significantly ( q < 1.3 × 10 −2 ) increased expression of Programed Cell Death, p53 downstream pathway , and target genes of transcription factors TP53, BRCA1 (breast cancer 1), PALB2 (partner and localizer of BRCA2), STAT3, CEBPA (CCAAT/enhancer binding protein alpha), and PPARG (peroxisome proliferator activated receptor gamma), and significant ( q < 1.3 × 10 −2 ) decreases of Muscle Contraction, Cholesterol Biosynthesis, Anatomical Structure Development , and target genes of SUZ12 (SUZ12 polycomb repressive complex 2 subunit), CTBP2 (C-terminal binding protein 2), EPAS1 (endothelial PAS domain protein 1), and RAD21 (RAD21 cohesin complex component) in DOXTOX hiPSC–CMs treated with 1 µM doxorubicin compared to the untreated group (Fig.…”

Section: Resultssupporting

confidence: 62%

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Burridge

Matsa

et al. 2016

Nat Med

606

506

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Doxorubicin (Adriamycin) is an anthracycline chemotherapy agent effective in treating a wide range of malignancies with a well–established dose–response cardiotoxic side effect that can lead to heart failure. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient–specific human induced pluripotent stem cell–derived cardiomyocytes (hiPSC–CMs) can recapitulate individual patients’ predilection to DIC at the single cell level. hiPSC–CMs derived from breast cancer patients who suffered clinical DIC are consistently more sensitive to doxorubicin toxicity, demonstrating decreased cell viability, mitochondrial and metabolic function, calcium handling, and antioxidant pathway activity, along with increased reactive oxygen species (ROS) production compared to hiPSC–CMs from patients who did not experience DIC. Together, our data indicate that hiPSC–CMs are a suitable platform for identifying and verifying the genetic basis and molecular mechanisms of DIC.

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Section: Resultssupporting

confidence: 62%

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Burridge

Matsa

et al. 2016

Nat Med

606

506

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“…Besides ROS, other inflammatory mediators, such as IL6, GM-CSF and IFNg were also found to upregulate the expression of TLR-4 in different published studies (43). Intriguingly, the expression of IL6, GM-CSF, and IFNg could all be enhanced by doxorubicin treatments in vivo or in vitro (44)(45)(46). Moreover, the upregulation of TLRs (including TLR4) seems a common phenomenon in the inflammation process as there is evidence that LPS, oxidative LDL and CpG could all increase the expression of some TLRs.…”

Section: Discussionmentioning

confidence: 91%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicininduced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. Ó2016 AACR.

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“…Etoposide, camptothecin and doxorubicin also caused a similar increase in IAP gene expression (Figure S5A). In addition, analysis of other microarray data sets (Altena et al, 2015; Hussner et al, 2012) revealed that induction of IAP genes after doxorubicin or cisplatin treatment occurs in other cancerous (HeLa, Figure S5B) and primary (HMEC-1, Figure S5C) cell lines. Together these results suggest that induction of IAP proteins by DNA damaging agents is not limited to cisplatin or HCT116 cells (Figure S5A–C).…”

Section: Resultsmentioning

confidence: 99%

Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing

Paek

Liu

Loewer

et al. 2016

Cell

275

304

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Summary Many chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon-cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell’s probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.

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Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

Cited by 25 publications

References 30 publications

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing

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