Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 45, Issue 6, Pages 2349-2354Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2014.2671
Keywords
osteosarcoma; cancer stem cells; proteasome activity
Categories
Funding
- Platform for Drug Discovery, Informatics, and Structural Life Science
- Ministry of Education, Culture, Sports, Science and Technology
- Third Comprehensive 10-Year Strategy for Cancer Control, Ministry of Health, Labour and Welfare, Japan
- Chugai Co., Ltd.
- Yakult Honsha Co., Ltd.
- Merck Co., Ltd.
- Taiho Therapeutic Co., Ltd.
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Osteosarcoma is the most common primary bone malignancy in pediatric and adolescent populations. Recurrence and metastatic potential can be due to a subpopulation of cells with stem cell-like characteristics, such as tumor-initiating cells (TICs), which maintain the capacity to regenerate entire tumors. Targeting the TICs in osteosarcoma is a promising avenue for the development of new therapies for this devastating disease. TICs are usually quiescent with a low protein turnover, decreased metabolism, and downregulation of proteasome activity. Recently, cancer cells with low proteasome activity have been identified as TICs in several types of cancer. We stably infected two osteosarcoma cell lines, MG-63 and U2-OS, with an expression vector for a fusion protein between the green fluorescent protein, Zs Green, and the C-terminal degron of the murine ornithine decarboxylase to monitor the 26S proteasome activity in living cells. We separated the osteosarcoma cells with low proteasome activity using fluorescence-activated cell sorting (FACS) and verified whether these Zs Green(+) cells had TIC-like properties. The Zs Green(+) cells showed enhanced sphere formation capacity and underwent asymmetric divisions into ZsGreen(+) and ZsGreen(-) cells, whereas ZsGreen(-) cells underwent only symmetric divisions into ZsGreen(-) cells. Moreover, the ZsGreen(+) cells were more chemo(-) and radioresistant. Thus, the present study demonstrated that chemoradiation-resistant TICs can be visualized by this system and suggested the rationale for further study of osteosarcoma stem cells.
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