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

Abstract

Summary 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 + CD44v 3 + gefitinib-resistant EGFR L858R/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.

Salinomycin as a potent anticancer stem cell agent: State of the art and future directions

“…A few research groups, including us, observed that salinomycin itself or by sensitizing chemodrugs or radiation, moderately or strongly increases DNA damage, inducing G2 arrest and reduction of p21 protein level in cancer cells 45,46,70–72 . In accord with these findings, we also further noticed the phosphorylation of tripartite motif‐containing 28 (TRIM28) along with salinomycin treatment in neuroblastoma cells (unpublished data).…”

“…Studies from us and also other groups have shown that salinomycin suppresses CSCs in many cancer types including breast cancer, 24 , 34 , 44 , 75 , 91 , 92 , 93 , 94 neuroblastoma, 51 GBM, 38 , 43 , 76 , 95 medulloblastoma, 71 pancreatic cancer, 20 , 37 , 96 colon cancer, 67 , 82 , 97 , 98 , 99 prostate cancer, 100 , 101 , 102 melanoma, 103 lung cancer, 72 , 104 and so on. Despite the above‐mentioned efforts, the cellular target of salinomycin remained unclear for a long time.…”

Acquired resistance to EGFR-TKIs in NSCLC mediates epigenetic downregulation of MUC17 by facilitating NF-κB activity via UHRF1/DNMT1 complex

“…However, members of the transmembrane mucins play opposite roles in drug resistance and tumor progression. Studies have shown that MUCs has a regulatory effect on EGFR 55 , 56 . The SEA domain of MUCs in drug-resistant cells were shed under the action of matrix metalloproteinase-7 (MMP-7), releasing MUC1-C-ter and promoting the nucleolus transport of p53 in gefitinib-resistant cells 55 .…”

“…Studies have shown that MUCs has a regulatory effect on EGFR 55 , 56 . The SEA domain of MUCs in drug-resistant cells were shed under the action of matrix metalloproteinase-7 (MMP-7), releasing MUC1-C-ter and promoting the nucleolus transport of p53 in gefitinib-resistant cells 55 . Here, we demonstrated a more complicated epigenetic regulation of MUC17 in lung cancer.…”

A Non‐G‐Quadruplex DNA Aptamer Targeting NCL for Diagnosis and Therapy in Bladder Cancer

“…[16] Drugs targeting NCL, such as salinomycin, can effectively kill CSCs, which is important for cancer drug-resistance therapy and prognosis. [17] The biological function of NCL in promoting cellular homeostasis is also responsible for the development of its malignant features under pathological conditions.…”