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p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

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Abstract

Purpose

Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22 % of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild-type p53 can increase chemosensitivity in MDR osteosarcoma cells.

Methods

We transfected a plasmid encoding the wild-type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild-type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities.

Results

Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53-induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly.

Conclusions

These results demonstrated that transfection of wild-type p53 increases chemosensitivity either through inhibiting IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines.

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Acknowledgements

This work was supported in part by grants from the Gattegno and Wechsler funds, the Stanton Foundation. Dr. Duan is supported, in part, through a grant from Sarcoma Foundation of America (SFA), a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA151452-01, a pilot grant from Sarcoma SPORE/NIH, and a grant from an Academic Enrichment Fund of MGH Orthopedic Surgery. The authors thank Yan Gao for assistance with densitometric analysis of Western blot results by Image J.

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Authors and Affiliations

  1. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St., Jackson 1115, Boston, MA, 02114, USA

    Shunan Ye, Jacson Shen, Edwin Choy, Henry Mankin, Francis Hornicek & Zhenfeng Duan

  2. Department of Orthopedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Shunan Ye & Cao Yang

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  1. Shunan Ye
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Correspondence to Zhenfeng Duan.

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Ye, S., Shen, J., Choy, E. et al. p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines. Cancer Chemother Pharmacol 77, 349–356 (2016). https://doi.org/10.1007/s00280-015-2944-z

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