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

Das, Dipon ; Preet, Ranjan ; Mohapatra, Purusottam ; Satapathy, Shakti Ranjan ; Siddharth, Sumit ; Tamir, Tigist ; Jain, Vaibhav ; Bharatam, Prasad V. ; Wyatt, Michael D. ; Kundu, Chanakya Nath (2014) 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 DNA Repair, 24 . pp. 15-25. ISSN 1568-7864

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Official URL: http://doi.org/10.1016/j.dnarep.2014.10.006

Related URL: http://dx.doi.org/10.1016/j.dnarep.2014.10.006

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 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.

Item Type:Article
Source:Copyright of this article belongs to Elsevier B.V.
Keywords:5-Fluorouracil (5-FU); Adenomatous Polyposis Coli (APC); Long Patch Base Excision Repair (LP-BER); Colorectal Cancer (CRC).
ID Code:116429
Deposited On:12 Apr 2021 09:40
Last Modified:12 Apr 2021 09:40

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