4.7 Article

Induction of autophagy promotes differentiation of glioma-initiating cells and their radiosensitivity

Journal

INTERNATIONAL JOURNAL OF CANCER
Volume 129, Issue 11, Pages 2720-2731

Publisher

WILEY-BLACKWELL
DOI: 10.1002/ijc.25975

Keywords

glioma-initiating cells; autophagy; differentiation; radiosensitization

Categories

Funding

  1. National Natural Science Foundation of China [30873052, 81072656]
  2. Natural Science Foundation of Jiangsu Province, China [BK2010226]
  3. Graduate Education Innovation Project of Jiangsu Province, China [CX10B_057Z]
  4. Soochow University [23320935]

Ask authors/readers for more resources

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. Recently, the identification of tumor-initiating cells with stem-like properties in diverse human cancers including GBM represents an important conceptual advance in cancer biology with therapeutic implications. However, the factors determining the differential development and radiosensitization of glioma-initiating cells (GICs) remain poorly defined. Here, we report that rapamycin induced differentiation of GICs and increased their sensitivity to radiation by activating autophagy. Transient in vitro exposure to rapamycin and radiation abolished the capacity of transplanted GICs to establish intracerebral GBMs. Most importantly, in vivo combination of rapamycin and radiation effectively blocked the tumor growth and associated mortality that occurs in mice after intracerebral grafting of human GICs. We demonstrate that rapamycin activated their autophagy and triggers the differentiation cascade in GICs isolated from human GBMs. This was followed by a reduction in proliferation, cell viability, clonogenic ability and increased expression of neural differentiation markers after radiation. Our results suggest that autophagy plays an essential role in the regulation of self-renewal, differentiation, tumorigenic potential and radiosensitization of GICs, suggesting autophagy could be a promising therapeutic target in a subset of GBMs. We propose that autophagy defect in GICs contributes to radioresistance of GICs by desensitizing GICs to normal differentiation cues. Activating autophagy may abrogate the resistance of GICs to radiation and could lead to the development of novel therapeutic approaches for the treatment of GBMs.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available