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p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

Shunan Ye1,2, Jacson Shen1, Edwin Choy1

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

Cancer Chemotherapy and Pharmacology
|December 25, 2015
PubMed
Abstract

Insights

Overexpressing wild-type p53 in multidrug-resistant osteosarcoma cells enhances chemotherapy sensitivity. This occurs by increasing pro-apoptotic proteins or decreasing IGF-1r, depending on the cell line's p53 status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Multidrug resistance (MDR) significantly impedes effective osteosarcoma chemotherapy.
  • The p53 tumor suppressor gene plays a crucial role in apoptosis, a key mechanism for cancer therapy effectiveness.
  • While p53 mutations are common in osteosarcoma, its role in enhancing chemosensitivity in MDR cells remains unclear.

Purpose of the Study:

  • To investigate whether overexpressing wild-type p53 can improve chemosensitivity in multidrug-resistant (MDR) osteosarcoma cell lines.
  • To determine the impact of wild-type p53 gene transfection on drug sensitivities in osteosarcoma cells with differing intrinsic p53 statuses.
  • To elucidate the molecular mechanisms by which p53 influences chemosensitivity in MDR osteosarcoma.

Main Methods:

  • Transfection of a plasmid encoding the wild-type p53 gene into two MDR osteosarcoma cell lines: U-2OSR2 (wild-type p53) and KHOSR2 (mutant p53).
  • Assessment of p53 overexpression effects on chemosensitivities in both cell lines.
  • Analysis of changes in the expression of key proteins, including p21, Bax, and IGF-1r.

Main Results:

  • Both cell lines showed increased drug sensitivities following p53 overexpression, though the specific mechanisms differed based on intrinsic p53 status.
  • In KHOSR2 (mutant p53) cells, p53 overexpression upregulated pro-apoptotic proteins p21 and Bax.
  • In U-2OSR2 (wild-type p53) cells, p53 overexpression significantly downregulated IGF-1r expression.

Conclusions:

  • Transfection of wild-type p53 enhances chemosensitivity in human multidrug-resistant osteosarcoma cell lines.
  • This chemosensitization is achieved either by inhibiting IGF-1r or by increasing the expression of pro-apoptotic proteins p21 and Bax.
  • The specific pathway activated by p53 depends on the cell line's endogenous p53 status, highlighting a potential therapeutic strategy for osteosarcoma.
Keywords:
ApoptosisMDROsteosarcomap53

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