Evaluating adaptive stress response gene signatures using transcriptomics

2021 ◽  
pp. 100179
Author(s):  
Bryant Chambers ◽  
Imran Shah
Keyword(s):  
Stress Response ◽  
Response Gene ◽  
Gene Signatures ◽  
Adaptive Stress Response ◽  
Stress Response Gene

scholarly journals Deuterium Oxide (D2O) Induces Early Stress Response Gene Expression and Impairs Growth and Metastasis of Experimental Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 605
Author(s):  
Jana Jandova ◽  
Anh B. Hua ◽  
Jocelyn Fimbres ◽  
Georg T. Wondrak
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Malignant Melanoma ◽  
Tumor Growth ◽  
Deuterium Oxide ◽  
Human Melanoma ◽  
Pharmacological Intervention ◽  
Melanoma Metastasis ◽  
Response Gene ◽  
Stress Response Gene

There are two stable isotopes of hydrogen, protium (1H) and deuterium (2H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact of deuterium (2H)-stress on cancer cells remain largely unexplored. We have examined the anti-proliferative and apoptogenic effects of deuterium oxide (D2O; ‘heavy water’) together with stress response gene expression profiling in panels of malignant melanoma (A375V600E, A375NRAS, G361, LOX-IMVI), and pancreatic ductal adenocarcinoma (PANC-1, Capan-2, or MIA PaCa-2) cells with inclusion of human diploid Hs27 skin fibroblasts. Moreover, we have examined the efficacy of D2O-based pharmacological intervention in murine models of human melanoma tumor growth and metastasis. D2O-induction of apoptosis was substantiated by AV-PI flow cytometry, immunodetection of PARP-1, and pro-caspase 3 cleavage, and rescue by pan-caspase inhibition. Differential array analysis revealed early modulation of stress response gene expression in both A375 melanoma and PANC-1 adenocarcinoma cells elicited by D2O (90%; ≤6 h) (upregulated: CDKN1A, DDIT3, EGR1, GADD45A, HMOX1, NFKBIA, or SOD2 (up to 9-fold; p < 0.01)) confirmed by independent RT-qPCR analysis. Immunoblot analysis revealed rapid onset of D2O-induced stress response phospho-protein activation (p-ERK, p-JNK, p-eIF2α, or p-H2AX) or attenuation (p-AKT). Feasibility of D2O-based chemotherapeutic intervention (drinking water (30% w/w)) was demonstrated in a severe combined immunodeficiency (SCID) mouse melanoma metastasis model using luciferase-expressing A375-Luc2 cells. Lung tumor burden (visualized by bioluminescence imaging) was attenuated by D2O, and inhibition of invasiveness was also confirmed in an in vitro Matrigel transwell invasion assay. D2O supplementation also suppressed tumor growth in a murine xenograft model of human melanoma, and median survival was significantly increased without causing adverse effects. These data demonstrate for the first time that systemic D2O administration impairs growth and metastasis of malignant melanoma through the pharmacological induction of deuterium (2H)-stress.

scholarly journals Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1904-1914 ◽  
Author(s):  
Hongfeng Yuan ◽  
Zhiqiang Wang ◽  
Ling Li ◽  
Hao Zhang ◽  
Hardik Modi ◽  
...  
Keyword(s):  
Stress Response ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Gene Knockout ◽  
Myelogenous Leukemia ◽  
Hematopoietic Progenitor Cells ◽  
Imatinib Treatment ◽  
Hematopoietic Progenitor ◽  
Response Gene ◽  
Stress Response Gene

Abstract The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but primary and acquired resistance of CML cells to the drug offset its efficacy. Molecular mechanisms for resistance of CML to tyrosine kinase inhibitors are not fully understood. In the present study, we show that BCR-ABL activates the expression of the mammalian stress response gene SIRT1 in hematopoietic progenitor cells and that this involves STAT5 signaling. SIRT1 activation promotes CML cell survival and proliferation associated with deacetylation of multiple SIRT1 substrates, including FOXO1, p53, and Ku70. Imatinib-mediated inhibition of BCR-ABL kinase activity partially reduces SIRT1 expression and SIRT1 inhibition further sensitizes CML cells to imatinib-induced apoptosis. Knockout of SIRT1 suppresses BCR-ABL transformation of mouse BM cells and the development of a CML-like myeloproliferative disease, and treatment of mice with the SIRT1 inhibitor tenovin-6 deters disease progression. The combination of SIRT1 gene knockout and imatinib treatment further extends the survival of CML mice. Our results suggest that SIRT1 is a novel survival pathway activated by BCR-ABL expression in hematopoietic progenitor cells, which promotes oncogenic transformation and leukemogenesis. Our findings suggest further exploration of SIRT1 as a therapeutic target for CML treatment to overcome resistance.

scholarly journals Solar simulated ultraviolet radiation inactivates HCoV-NL63 and SARS-CoV-2 coronaviruses at environmentally relevant doses

2021 ◽  
Author(s):  
Georg T. Wondrak ◽  
Jana Jandova ◽  
Spencer J. Williams ◽  
Dominik Schenten
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Uv Light ◽  
Gene Expression Array ◽  
Array Analysis ◽  
Expression Array ◽  
Response Gene ◽  
Full Spectrum ◽  
Solar Uv ◽  
Stress Response Gene

The germicidal properties of short wavelength ultraviolet C (UVC) light are well established and used to inactivate many viruses and other microbes. However, much less is known about germicidal effects of terrestrial solar UV light, confined exclusively to wavelengths in the UVA and UVB regions. Here, we have explored the sensitivity of the human coronaviruses HCoV-NL63 and SARS-CoV-2 to solar-simulated full spectrum ultraviolet light (sUV) delivered at environmentally relevant doses. First, HCoV-NL63 coronavirus inactivation by sUV-exposure was confirmed employing (i) viral plaque assays, (ii) RT-qPCR detection of viral genome replication, and (iii) infection-induced stress response gene expression array analysis. Next, a detailed dose-response relationship of SARS-CoV-2 coronavirus inactivation by sUV was elucidated, suggesting a half maximal suppression of viral infectivity at low sUV doses. Likewise, extended sUV exposure of SARS-CoV-2 blocked cellular infection as revealed by plaque assay and stress response gene expression array analysis. Moreover, comparative (HCoV-NL63 versus SARS-CoV-2) single gene expression analysis by RT-qPCR confirmed that sUV exposure blocks coronavirus-induced redox, inflammatory, and proteotoxic stress responses. Based on our findings, we estimate that solar ground level full spectrum UV light impairs coronavirus infectivity at environmentally relevant doses. Given the urgency and global scale of the unfolding SARS-CoV-2 pandemic, these prototype data suggest feasibility of solar UV-induced viral inactivation, an observation deserving further molecular exploration in more relevant exposure models.

scholarly journals Ezrin Inhibition Up-regulates Stress Response Gene Expression

2016 ◽  
Vol 291 (25) ◽  
pp. 13257-13270 ◽  
Author(s):  
Haydar Çelik ◽  
Gülay Bulut ◽  
Jenny Han ◽  
Garrett T. Graham ◽  
Tsion Z. Minas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Response Gene ◽  
Stress Response Gene

Inflammation, signaling, DNA repair and stress response gene expression during placental development

2006 ◽  
Vol 71 (2) ◽  
pp. 159 ◽  
Author(s):  
M. Meller ◽  
D. Abetew ◽  
C. Qiu ◽  
S. Vadachkoria ◽  
D. Luthy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Stress Response ◽  
Placental Development ◽  
Response Gene ◽  
Stress Response Gene

scholarly journals Endogenous rRNA Sequence Variation Can Regulate Stress Response Gene Expression and Phenotype

Cell Reports ◽  
2018 ◽  
Vol 25 (1) ◽  
pp. 236-248.e6 ◽  
Author(s):  
Chad M. Kurylo ◽  
Matthew M. Parks ◽  
Manuel F. Juette ◽  
Boris Zinshteyn ◽  
Roger B. Altman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Sequence Variation ◽  
Rrna Sequence ◽  
Response Gene ◽  
Stress Response Gene

Abstract 211: ATF6 and the Adaptive ER Stress Response Enhances Proliferation and Viability in Mouse Cardiac Stem Cells

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Winston T Stauffer ◽  
Shirin Doroudgar ◽  
Haley N Stephens ◽  
Brandi Bailey ◽  
Christopher C Glembotski
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stress Response ◽  
Er Stress ◽  
Ischemic Heart ◽  
Cardiac Stem Cells ◽  
Response Gene ◽  
Er Stress Response ◽  
Chemical Inhibition ◽  
Stress Response Gene

Rationale: Cardiac stem cells (CSCs) are beneficial when administered to infarcted mouse or rat hearts. Though the mechanism of these benefits is unknown, CSC vitality likely plays a major role. Thus, investigating the factors governing CSC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CSCs. We hypothesize that ATF6 and the adaptive ER stress response are critical for optimal survival of CSCs. Objective/Methods: To gauge the relevance of the ER stress response in CSCs, we used MTT assays to compare the viabilities of mouse CSCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We also assessed the effect of inhibiting ATF6 on both the ER stress response and CSC viability by using chemical inhibition of ATF6 activation or siRNA-mediated ATF6 knock down. Results: We found that, compared to NRVM, CSCs exhibited lower levels of adaptive ER stress response gene expression and decreased viability in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CSCs. We also found that either chemical inhibition of ATF6 activation or ATF6 knock down decreased adaptive ER stress response gene expression. Strikingly, ATF6 inhibition or knockdown decreased CSC viability and cell number by as much as 70%. Conclusions: Thus, compared to cardiac myocytes, CSCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CSCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.

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