Using Phenomic Analysis of Photosynthetic Function for Abiotic Stress Response Gene Discovery

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.

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The Raf-like kinase ILK1 and the high affinity K+ transporter HAK5 are required for Innate Immunity and Abiotic Stress Response

PLANT PHYSIOLOGY ◽

10.1104/pp.16.00035 ◽

2016 ◽

pp. pp.00035.2016 ◽

Cited By ~ 11

Author(s):

Elizabeth Kalinda Brauer ◽

Nagib Ahsan ◽

Renee Dale ◽

Naohiro Kato ◽

Alison E Coluccio ◽

...

Keyword(s):

Innate Immunity ◽

Abiotic Stress ◽

Stress Response ◽

Abiotic Stress Response ◽

High Affinity

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

Blood ◽

10.1182/blood-2011-06-361691 ◽

2012 ◽

Vol 119 (8) ◽

pp. 1904-1914 ◽

Cited By ~ 100

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.

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