Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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
Doi: 10.1038/onc.2014.372
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- Führende Autor*innen der Med Uni Graz
- Ravindran Menon Dinoop
- Schaider Helmut
- Co-Autor*innen der Med Uni Graz
- Bonyadirad Ehsan
- Das Suman Kumar
- Höfler Gerald
- Kashofer Karl
- Rinner Beate
- Schauer Silvia
- Soyer Hans Peter
- Wagner Karin
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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 -