5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of Adenomatous Polyposis Coli : Implication of the long-patch base excision repair pathway
(2014) In DNA Repair 24. p.15-25- Abstract
Colorectal cancer (CRC) patients with APC mutations do not benefit from 5-FU therapy. It was reported that APC physically interacts with POLβ and FEN1, thus blocking LP-BER via APC's DNA repair inhibitory (DRI) domain in vitro. The aim of this study was to elucidate how APC status affects BER and the response of CRC to 5-FU. HCT-116, HT-29, and LOVO cells varying in APC status were treated with 5-FU to evaluate expression, repair, and survival responses. HCT-116 expresses wild-type APC; HT-29 expresses an APC mutant that contains DRI domain; LOVO expresses an APC mutant lacking DRI domain. 5-FU increased the expression of APC and decreased the expression of FEN1 in HCT-116 and HT-29 cells, which were sensitized to 5-FU when compared to... (More)
Colorectal cancer (CRC) patients with APC mutations do not benefit from 5-FU therapy. It was reported that APC physically interacts with POLβ and FEN1, thus blocking LP-BER via APC's DNA repair inhibitory (DRI) domain in vitro. The aim of this study was to elucidate how APC status affects BER and the response of CRC to 5-FU. HCT-116, HT-29, and LOVO cells varying in APC status were treated with 5-FU to evaluate expression, repair, and survival responses. HCT-116 expresses wild-type APC; HT-29 expresses an APC mutant that contains DRI domain; LOVO expresses an APC mutant lacking DRI domain. 5-FU increased the expression of APC and decreased the expression of FEN1 in HCT-116 and HT-29 cells, which were sensitized to 5-FU when compared to LOVO cells. Knockdown of APC in HCT-116 rendered cells resistant to 5-FU, and FEN1 levels remained unchanged. Re-expression of full-length APC in LOVO cells caused sensitivity to 5-FU, and decreased expression of FEN1. These knockdown and addback studies confirmed that the DRI domain is necessary for the APC-mediated reduction in LP-BER and 5-FU. Modelling studies showed that 5-FU can interact with the DRI domain of APC via hydrogen bonding and hydrophobic interactions. 5-FU resistance in CRC occurs with mutations in APC that disrupt or eliminate the DRI domain's interaction with LP-BER. Understanding the type of APC mutation should better predict 5-FU resistance in CRC than simply characterizing APC status as wild-type or mutant.
(Less)
- author
- Das, Dipon ; Preet, Ranjan ; Mohapatra, Purusottam LU ; Satapathy, Shakti Ranjan LU ; Siddharth, Sumit ; Tamir, Tigist ; Jain, Vaibhav ; Bharatam, Prasad V ; Wyatt, Michael D and Kundu, Chanakya Nath
- publishing date
- 2014-12
- type
- Contribution to journal
- publication status
- published
- keywords
- Adenomatous Polyposis Coli Protein/chemistry, Amino Acid Sequence, Antimetabolites, Antineoplastic/pharmacology, Cell Line, Tumor/drug effects, Colonic Neoplasms/drug therapy, DNA Repair/drug effects, Flap Endonucleases/metabolism, Fluorouracil/pharmacology, Gene Knockdown Techniques, HCT116 Cells/drug effects, Humans, Hydrogen Bonding, Molecular Docking Simulation, Molecular Sequence Data, Proteasome Endopeptidase Complex/metabolism, Protein Structure, Tertiary
- in
- DNA Repair
- volume
- 24
- pages
- 15 - 25
- publisher
- Elsevier
- external identifiers
-
- pmid:25460919
- scopus:84910035474
- ISSN
- 1568-7856
- DOI
- 10.1016/j.dnarep.2014.10.006
- language
- English
- LU publication?
- no
- id
- 31bd0eb0-638d-4b4d-b44b-8becb4ef8feb
- date added to LUP
- 2025-01-30 10:33:36
- date last changed
- 2025-06-06 13:57:12
@article{31bd0eb0-638d-4b4d-b44b-8becb4ef8feb,
abstract = {{<p>Colorectal cancer (CRC) patients with APC mutations do not benefit from 5-FU therapy. It was reported that APC physically interacts with POLβ and FEN1, thus blocking LP-BER via APC's DNA repair inhibitory (DRI) domain in vitro. The aim of this study was to elucidate how APC status affects BER and the response of CRC to 5-FU. HCT-116, HT-29, and LOVO cells varying in APC status were treated with 5-FU to evaluate expression, repair, and survival responses. HCT-116 expresses wild-type APC; HT-29 expresses an APC mutant that contains DRI domain; LOVO expresses an APC mutant lacking DRI domain. 5-FU increased the expression of APC and decreased the expression of FEN1 in HCT-116 and HT-29 cells, which were sensitized to 5-FU when compared to LOVO cells. Knockdown of APC in HCT-116 rendered cells resistant to 5-FU, and FEN1 levels remained unchanged. Re-expression of full-length APC in LOVO cells caused sensitivity to 5-FU, and decreased expression of FEN1. These knockdown and addback studies confirmed that the DRI domain is necessary for the APC-mediated reduction in LP-BER and 5-FU. Modelling studies showed that 5-FU can interact with the DRI domain of APC via hydrogen bonding and hydrophobic interactions. 5-FU resistance in CRC occurs with mutations in APC that disrupt or eliminate the DRI domain's interaction with LP-BER. Understanding the type of APC mutation should better predict 5-FU resistance in CRC than simply characterizing APC status as wild-type or mutant.</p>}},
author = {{Das, Dipon and Preet, Ranjan and Mohapatra, Purusottam and Satapathy, Shakti Ranjan and Siddharth, Sumit and Tamir, Tigist and Jain, Vaibhav and Bharatam, Prasad V and Wyatt, Michael D and Kundu, Chanakya Nath}},
issn = {{1568-7856}},
keywords = {{Adenomatous Polyposis Coli Protein/chemistry; Amino Acid Sequence; Antimetabolites, Antineoplastic/pharmacology; Cell Line, Tumor/drug effects; Colonic Neoplasms/drug therapy; DNA Repair/drug effects; Flap Endonucleases/metabolism; Fluorouracil/pharmacology; Gene Knockdown Techniques; HCT116 Cells/drug effects; Humans; Hydrogen Bonding; Molecular Docking Simulation; Molecular Sequence Data; Proteasome Endopeptidase Complex/metabolism; Protein Structure, Tertiary}},
language = {{eng}},
pages = {{15--25}},
publisher = {{Elsevier}},
series = {{DNA Repair}},
title = {{5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of Adenomatous Polyposis Coli : Implication of the long-patch base excision repair pathway}},
url = {{http://dx.doi.org/10.1016/j.dnarep.2014.10.006}},
doi = {{10.1016/j.dnarep.2014.10.006}},
volume = {{24}},
year = {{2014}},
}