PMID- 38314724
OWN - NLM
STAT- MEDLINE
DCOM- 20240313
LR  - 20240313
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Linking)
VI  - 326
IP  - 4
DP  - 2024 Apr 1
TI  - Everolimus exerts anticancer effects through inhibiting the interaction of matrix 
      metalloproteinase-7 with syndecan-2 in colon cancer cells.
PG  - C1067-C1079
LID - 10.1152/ajpcell.00669.2023 [doi]
AB  - Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon 
      cancer activities through an interaction with syndecan-2 (SDC-2) and 
      SDC-2-derived peptide that disrupts this interaction and exhibits anticancer 
      activity in colon cancer. Here, to identify potential anticancer agents, a 
      library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact 
      with the MMP-7 prodomain were virtually screened by protein-ligand docking score 
      analysis using the GalaxyDock3 program. Among five candidates selected based on 
      their structures and total energy values for interacting with the MMP-7 
      prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, 
      everolimus, showed the highest binding affinity and the strongest ability to 
      disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular 
      domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line 
      did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the 
      adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface 
      localization of MMP-7. Thus, everolimus appears to inhibit the interaction 
      between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their 
      gelatin-degradation activity and anticancer activities, including colony 
      formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, 
      triggered less gelatin-degradation activity, suggesting that this inhibitory 
      effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, 
      everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. 
      Together, these data suggest that, in addition to inhibiting mTOR signaling, 
      everolimus exerts anticancer activity by interfering with the interaction of 
      MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon 
      cancer.NEW & NOTEWORTHY The utility of cancer therapeutics targeting the 
      proteolytic activities of MMPs is limited because MMPs are widely distributed 
      throughout the body and involved in many different aspects of cell functions. 
      This work specifically targets the activation of MMP-7 through its interaction 
      with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this 
      interaction, demonstrating a novel role for everolimus in inhibiting mTOR 
      signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.
FAU - Lee, Seohyeon
AU  - Lee S
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Jang, Bohee
AU  - Jang B
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Hwang, Jisun
AU  - Hwang J
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Lee, Yejin
AU  - Lee Y
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Cho, Subin
AU  - Cho S
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Yang, Hyeonju
AU  - Yang H
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
FAU - Yun, Ji-Hye
AU  - Yun JH
AD  - PCG-Biotech, Ltd. Yonsei Engineering Research Park 114A, Yonsei University, 
      Seoul, Republic of Korea.
AD  - Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of 
      Korea.
FAU - Shin, Dong Hae
AU  - Shin DH
AD  - College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
FAU - Lee, Weontae
AU  - Lee W
AD  - PCG-Biotech, Ltd. Yonsei Engineering Research Park 114A, Yonsei University, 
      Seoul, Republic of Korea.
FAU - Oh, Eok-Soo
AU  - Oh ES
AUID- ORCID: 0000-0001-8908-6821
AD  - Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea. 
      ROR: https://ror.org/053fp5c05
LA  - eng
PT  - Journal Article
DEP - 20240205
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 9HW64Q8G6G (Everolimus)
RN  - 149769-25-5 (Syndecan-2)
RN  - EC 3.4.24.23 (Matrix Metalloproteinase 7)
RN  - 9000-70-8 (Gelatin)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - *Everolimus/pharmacology
MH  - Syndecan-2/genetics/metabolism
MH  - Matrix Metalloproteinase 7/genetics/metabolism
MH  - Gelatin
MH  - Sirolimus/pharmacology
MH  - *Colonic Neoplasms/drug therapy/metabolism
MH  - TOR Serine-Threonine Kinases
OTO - NOTNLM
OT  - colon cancer
OT  - everolimus
OT  - matrix metalloproteinase-7
OT  - protein drug interaction
OT  - syndecan 2
EDAT- 2024/02/05 14:44
MHDA- 2024/03/13 06:47
CRDT- 2024/02/05 08:42
PHST- 2024/03/13 06:47 [medline]
PHST- 2024/02/05 14:44 [pubmed]
PHST- 2024/02/05 08:42 [entrez]
AID - 10.1152/ajpcell.00669.2023 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2024 Apr 1;326(4):C1067-C1079. doi: 
      10.1152/ajpcell.00669.2023. Epub 2024 Feb 5.