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Neurological Sciences

, Volume 34, Issue 8, pp 1421–1428 | Cite as

Mutant TP53 enhances the resistance of glioblastoma cells to temozolomide by up-regulating O6-methylguanine DNA-methyltransferase

  • Xiang Wang
  • Jin-xiu Chen
  • Yan-hui Liu
  • Chao You
  • Qing MaoEmail author
Original Article

Abstract

The “gain of function” of mutant TP53 is an important determinant in human tumor development and progression. This study aimed to investigate the possible mechanism of mutant TP53 inducing temozolomide resistance in glioblastoma cells. Three established human glioma cell lines, T98G, U87, and U138, were chemoresistant cells. The mRNA of cells was sequenced to confirm the status of TP53. Synthetic small interfering RNA (siRNA) was used to knock down TP53 in cells. TP53 mRNA was detected “silenced” by reverse transcriptase-polymerase chain reaction (RT-PCR) in five consecutive days. Viable cell survival was measured when these cells were exposed to temozolomide or semustine in step-up concentrations. The expression of O6-methylguanine DNA-methyltransferase (MGMT) at mRNA level was also determined. T98G, U87, and U138 cells were resistant to temozolomide. T98G and U138 cells expressed mutant-type TP53 with positive MGMT, while U87 cell expressed wild-type TP53 with negative MGMT. TP53-siRNA knocked down TP53 effectively (P = 0.021) in five consecutive days. Knockdown of mutant TP53 in T98G and U138 cells led to a fivefold increase in chemosensitivity to temozolomide, but not semustine. Knockdown of wild TP53 in U87 cell did not affect the chemoresistance. In addition, mutant TP53 knockdown induced a dramatic decrease of MGMT expression (P = 0.0000034). TP53 mutation decreases the chemosensitivity of malignant gliomas to temozolomide. This “gain of function” in drug resistance may be obtained by increasing MGMT expression.

Keywords

Drug resistance Glioblastoma Mutation RNA interference Tumor suppressor protein p53 

Notes

Conflict of interest

The authors declare that they have no conflict of interests.

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Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • Xiang Wang
    • 1
  • Jin-xiu Chen
    • 2
  • Yan-hui Liu
    • 1
  • Chao You
    • 1
  • Qing Mao
    • 1
    Email author
  1. 1.Department of NeurosurgeryWest China Hospital, Sichuan UniversityChengduChina
  2. 2.Department of RadiologySichuan Cancer HospitalChengduChina

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