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Activation of RARα induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity.

  • Brigger D Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
  • Schläfli AM Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
  • Garattini E Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy.
  • Tschan MP Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
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  • 2015-08-28
Published in:
  • Cell death & disease. - 2015
Antineoplastic Agents
Apoptosis
Autophagy
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Cell Differentiation
Cell Line, Tumor
Chloroquine
Drug Resistance, Neoplasm
Epithelial Cells
Female
Gene Expression Regulation, Neoplastic
Humans
Macrolides
Mammary Glands, Human
Microtubule-Associated Proteins
RNA, Small Interfering
Receptors, Retinoic Acid
Retinoic Acid Receptor alpha
Signal Transduction
Tretinoin
Ubiquitin-Activating Enzymes
English All-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, is, along with other retinoids, a promising therapeutic agent for the treatment of a variety of solid tumors. On the one hand, preclinical studies have shown promising anticancer effects of ATRA in breast cancer; on the other hand, resistances occurred. Autophagy is a cellular recycling process that allows the degradation of bulk cellular contents. Tumor cells may take advantage of autophagy to cope with stress caused by anticancer drugs. We therefore wondered if autophagy is activated by ATRA in mammary tumor cells and if modulation of autophagy might be a potential novel treatment strategy. Indeed, ATRA induces autophagic flux in ATRA-sensitive but not in ATRA-resistant human breast cancer cells. Moreover, using different RAR agonists as well as RARα-knockdown breast cancer cells, we demonstrate that autophagy is dependent on RARα activation. Interestingly, inhibition of autophagy in breast cancer cells by either genetic or pharmacological approaches resulted in significantly increased apoptosis under ATRA treatment and attenuated epithelial differentiation. In summary, our findings demonstrate that ATRA-induced autophagy is mediated by RARα in breast cancer cells. Furthermore, inhibition of autophagy results in enhanced apoptosis. This points to a potential novel treatment strategy for a selected group of breast cancer patients where ATRA and autophagy inhibitors are applied simultaneously.
Language
  • English
Open access status
gold
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Persistent URL
https://folia.unifr.ch/global/documents/241629
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