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Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer

Wei-Hsuan Yu1,2, Erxi Wu3,4,5, Yongqing Li6

  • 1Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Iscience
|October 22, 2020
PubMed

Insights

Matrix metalloproteinase-7 (MMP-7) and MUC-1 C-ter facilitate p53 transport to the nucleolus in cancer stem cells (CSCs). Targeting this MMP-7-MUC-1-p53 axis may overcome chemotherapy resistance in CSCs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cancer stem cells (CSCs) often exhibit enlarged nucleoli, but the mechanisms remain unclear.
  • Gefitinib-resistant lung CSCs present a significant challenge in cancer therapy.
  • The role of nucleolar structure in cancer progression and drug resistance is an emerging area of research.

Purpose of the Study:

  • To elucidate the mechanism behind the enlarged nucleolus in cancer stem cells.
  • To investigate the role of matrix metalloproteinase-7 (MMP-7) and MUC-1 in nucleolar function and p53 trafficking.
  • To identify potential therapeutic targets for overcoming chemotherapy resistance in CSCs.

Main Methods:

  • Analysis of nucleolus matrix assembly in cancer stem cells.
  • Investigating the interaction between MMP-7, MUC-1 C-ter, and p53 using immunofluorescence and cell biology techniques.
  • Assessing the effect of salinomycin on nucleolar structure and p53 localization in CSCs.

Main Results:

  • MMP-7 shedding of MUC-1 SEA domain releases MUC-1 C-ter, promoting p53 nucleolar trafficking in resistant CSCs.
  • A unique, bulky-ball-shaped nucleolus acts as a "garage" for p53 and facilitates its processing by MMP-7.
  • Salinomycin disrupts the nucleolus, causing p53 translocation and sensitizing CSCs to chemotherapy.

Conclusions:

  • The MMP-7-MUC-1-p53 axis within the nucleolus is crucial for CSC survival and chemoresistance.
  • Targeting this nucleolar pathway offers a potential strategy to overcome chemotherapy resistance.
  • Disruption of nucleolar function presents a novel therapeutic approach against cancer stem cells.
Keywords:
CancerCell BiologyMolecular Biology

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