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

The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34+ CXADR+ CD44v3+ gefitinib-resistant EGFRL858R/T790M CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular “garage” for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma. [Display omitted] •MMP-7 cleaves the SEA domain of MUC-1 and releases MUC-1 C-ter•MUC-1 C-ter mediates bulky-ball-like nucleolus assembly trapping p53 in nucleolus•MMP-7 cleaves p53 to 35 kDa fragments in the nucleolus of gefitinib-resistant CSCs•Salinomycin induces p53 nucleoplasm translocation sensitizing CSCs to gefitinib Molecular Biology; Cell Biology; Cancer