Simvastatin enhances the radiosensitivity of p53-deficient cells via inhibition of mouse double minute 2 homolog

Ji Young Lee, Mi Sook Kim, Jae Eun Ju, Mi So Lee, Namhyun Chung, Youn Kyoung Jeong

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Simvastatin exhibits anticancer activities, but its molecular mechanisms and radiosensitizing effects relative to p53 status remain unclear. In this study, we investigated whether the combination of simvastatin and ionizing radiation (IR) would enhance the antitumor effects of IR alone in HCT116 p53+/+ and p53-/- colon cancer cells. Using colony formation assays and a xenograft mouse model, we found that simvastatin potently stimulated radiosensitization of HCT116 p53-/- cells and xenograft tumors. The combination of simvastatin with IR decreased G2/M arrest and delayed the repair of IR-induced DNA damage; however, no differences between the HCT116 p53+/+ and p53-/- cells were evident. A further analysis revealed that simvastatin exhibited a novel function, namely, MDM2 suppression, regardless of p53 status. Interestingly, simvastatin induced radiosensitization by enhancing MDM2 suppression and elevating IR-induced p.ATM foci formation compared with IR alone in HCT116 p53-/- cells. Furthermore, simvastatin caused accumulations of the FOXO3a, E-cadherin, and p21 tumor suppressor proteins, which are downstream factors of MDM2, in HCT116 p53-/- cells. In conclusion, simvastatin enhanced radiosensitivity by inducing MDM2 inhibition and increasing tumor suppressor protein levels in radioresistant HCT116 p53-/- cells and xenografts. Overall, our novel findings suggest a scientific rationale for the clinical use of simvastatin as an MDM2 inhibitor and radiosensitizer for p53-deficient colorectal tumor treatments.

Original languageEnglish
Pages (from-to)211-218
Number of pages8
JournalInternational Journal of Oncology
Volume52
Issue number1
DOIs
Publication statusPublished - 2018 Jan 1

Keywords

  • DNA damage repair
  • MDM2 inhibitor
  • P53
  • Radiosensitizer
  • Simvastatin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Simvastatin enhances the radiosensitivity of p53-deficient cells via inhibition of mouse double minute 2 homolog'. Together they form a unique fingerprint.

  • Cite this