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SHR Neuro Krebs Kardio Lipid

Ravindran Menon, D; Das, S; Krepler, C; Vultur, A; Rinner, B; Schauer, S; Kashofer, K; Wagner, K; Zhang, G; Bonyadi Rad, E; Haass, NK; Soyer, HP; Gabrielli, B; Somasundaram, R; Hoefler, G; Herlyn, M; Schaider, H.
A stress-induced early innate response causes multidrug tolerance in melanoma.
Oncogene. 2015; 34(34):4448-4459 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bonyadirad Ehsan
Das Suman Kumar
Hoefler Gerald
Kashofer Karl
Ravindran Menon Dinoop
Rinner Beate
Schaider Helmut
Schauer Silvia
Soyer Hans Peter
Wagner Karin
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Number of Figures: 7
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Abstract:
Acquired drug resistance constitutes a major challenge for effective cancer therapies with melanoma being no exception. The dynamics leading to permanent resistance are poorly understood but are important to design better treatments. Here we show that drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multidrug resistance, termed induced drug-tolerant cells (IDTCs). Transition into the IDTC state seems to be an inherent stress reaction for survival toward unfavorable environmental conditions or drug exposure. The response comprises chromatin remodeling, activation of signaling cascades and markers implicated in cancer stemness with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced aldehyde dehydrogenase (ALDH) activity and upregulation of histone demethylases. Accordingly, IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3 suggesting activation and repression of differential genes. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. However, upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug-resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Drug Resistance, Multiple -
Drug Resistance, Neoplasm -
Humans -
Jumonji Domain-Containing Histone Demethylases - physiology
Melanoma - drug therapy
Mice -
Nerve Tissue Proteins - analysis
Nerve Tissue Proteins - physiology
Nuclear Proteins - physiology
Pyridones - therapeutic use
Pyrimidinones - therapeutic use
Receptors, Nerve Growth Factor - analysis
Receptors, Nerve Growth Factor - physiology
Repressor Proteins - physiology
Signal Transduction -
Stress, Physiological -

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