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One-step Protocol for Evaluation of the Mode of Radiation-induced Clonogenic Cell Death by Fluorescence Microscopy
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Effect of Functional Inhibition of BACE1 on Sensitization to γ-Irradiation in Cancer Cells

Keitaro Nakamoto1, Sota Kikuhara2,3, Hiroaki Fujimori1,2

  • 1Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.

Current Issues in Molecular Biology
|January 22, 2024
PubMed

Insights

Inhibiting beta-site of amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) can sensitize cancer cells to radiation therapy. BACE1 inhibition shows promise for improving radiotherapy, especially in cancers with p53 dysfunction.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Radiotherapy is a cornerstone of cancer treatment.
  • Developing strategies to enhance radiation sensitivity in cancer cells while minimizing toxicity to normal tissues is crucial.
  • Beta-site of amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) has been implicated in DNA damage response pathways.

Purpose of the Study:

  • To investigate the role of BACE1 in cellular response to ionizing radiation.
  • To evaluate the potential of BACE1 inhibition as a radiosensitizing strategy in cancer cells.
  • To explore the relationship between BACE1 knockdown, p53 status, and radiosensitivity.

Main Methods:

  • Knockdown of BACE1 using small interfering RNA (siRNA) in various cancer cell lines (HeLa, MDA-MB-231, U2OS, SAOS).
  • Assessment of radiosensitization through colony formation assays.
  • Analysis of DNA damage response markers, including gamma-H2AX foci and levels.
  • Flow cytometry to evaluate cell cycle effects and apoptosis.

Main Results:

  • BACE1 knockdown sensitized multiple cancer cell lines (HeLa, MDA-MB-231, U2OS, SAOS) to gamma-irradiation.
  • The radiosensitization effect varied among cell lines.
  • Cells with dysfunctional p53 (HeLa, SAOS) exhibited a greater degree of radiosensitization compared to cells with normal p53 function (U2OS).
  • BACE1 inhibition was associated with increased DNA damage response markers.

Conclusions:

  • BACE1 is a potential target for radiosensitization in cancer therapy.
  • The efficacy of BACE1 inhibition for radiosensitization may be dependent on the p53 status of the cancer cells.
  • Targeting BACE1 could offer a novel approach to improve the effectiveness of radiotherapy for specific cancer types.
Keywords:
BACE1cancer cellradiosensitizationγ-H2AXγ-irradiation

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