Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells View Full Text


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Article Info

DATE

2017-07-20

AUTHORS

Anna Pagotto, Giorgia Pilotto, Elena Laura Mazzoldi, Maria Ornella Nicoletto, Simona Frezzini, Anna Pastò, Alberto Amadori

ABSTRACT

Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors with a high mortality rate owing to tumor relapse after anticancer therapies. It is widely accepted that a rare tumor cell population, known as cancer stem cells (CSC), is responsible for tumor progression and relapse; intriguingly, these cells are able to survive nutrient starvation (such as in vitro culture in the absence of glucose) and chemotherapy treatment. Recent data also indicated that chemotherapy resistance is associated with autophagy activation. We thus decided to investigate both in vitro and in vivo the autophagic activity and the effects of the perturbation of this pathway in CSC isolated from EOC ascitic effusions. Ovarian CSC, identified according to their CD44/CD117 co-expression, presented a higher basal autophagy compared with the non-stem counterpart. Inhibition of this pathway, by in vitro chloroquine treatment or CRISPR/Cas9 ATG5 knockout, impaired canonical CSC properties, such as viability, the ability to form spheroidal structures in vitro, and in vivo tumorigenic potential. In addition, autophagy inhibition showed a synergistic effect with carboplatin administration on both in vitro CSC properties and in vivo tumorigenic activity. On the whole, these results indicate that the autophagy process has a key role in CSC maintenance; inhibition of this pathway in combination with other chemotherapeutic approaches could represent a novel effective strategy to overcome drug resistance and tumor recurrence. More... »

PAGES

e2943

References to SciGraph publications

  • 2012-04-23. The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells in ONCOGENE
  • 2012-06-25. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells in ONCOGENE
  • 2005-09. Migrating cancer stem cells — an integrated concept of malignant tumour progression in NATURE REVIEWS CANCER
  • 2014-07-30. Improved vectors and genome-wide libraries for CRISPR screening in NATURE METHODS
  • 2012-04-26. Deconvoluting the context-dependent role for autophagy in cancer in NATURE REVIEWS CANCER
  • 2010-09. Eaten alive: a history of macroautophagy in NATURE CELL BIOLOGY
  • 2013-10-10. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment in CELL DEATH & DISEASE
  • 2013-08-01. Emerging role of cancer stem cells in the biology and treatment of ovarian cancer: basic knowledge and therapeutic possibilities for an innovative approach in JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
  • 2010-03-01. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells in ONCOGENE
  • 2011-07-11. NAC1 Modulates Sensitivity of Ovarian Cancer Cells to Cisplatin via Altering the HMGB1-Mediated Autophagic Response* in ONCOGENE
  • 2015-10-12. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine in MOLECULAR CANCER
  • 2011-03-07. The cancer stem cell: premises, promises and challenges in NATURE MEDICINE
  • 2014-09-26. Oxidative stress and autophagy: the clash between damage and metabolic needs in CELL DEATH & DIFFERENTIATION
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/cddis.2017.327

    DOI

    http://dx.doi.org/10.1038/cddis.2017.327

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1090829695

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28726781


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