Oncotarget

Research Papers:

Cross resistance to diverse anticancer nicotinamide phosphoribosyltransferase inhibitors induced by FK866 treatment

Yoko Ogino _, Akira Sato, Fumiaki Uchiumi and Sei-Ichi Tanuma

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Oncotarget. 2018; 9:16451-16461. https://doi.org/10.18632/oncotarget.24731

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Abstract

Yoko Ogino1, Akira Sato1, Fumiaki Uchiumi1 and Sei-ichi Tanuma1

1Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan

Correspondence to:

Akira Sato, email: akirasat@rs.tus.ac.jp

Sei-ichi Tanuma, email: tanuma@rs.noda.tus.ac.jp

Keywords: drug resistance; FK866; NAD+ biosynthesis; NAMPT; point mutation

Received: January 26, 2018     Accepted: February 25, 2018     Published: March 27, 2018

ABSTRACT

Cross-resistance to drugs remains an unsolved problem in cancer chemotherapy. This study elucidates a molecular mechanism of cross-resistance to diverse inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) with anticancer activity. We generated a variant of the human colon cancer cell line HCT116, HCT116RFK866, which exhibited primary resistance to the potent NAMPT inhibitor FK866, and was approximately 1,000-fold less sensitive to the drug than the parental HCT116. HCT116RFK866 was found to be cross-resistant to diverse NAMPT inhibitors, including CHS-828, GNE-617, and STF-118804. Whole-exon sequencing revealed two point mutations (H191R and K342R) in NAMPT in HCT116RFK866, only one of which (K342R) was present in the parental HCT116. Importantly, the protein level, NAMPT enzyme activity, and intracellular NAD+ level were similar between HCT116RFK866 and HCT116. Hence, we investigated NAMPT-binding partners in both cell lines by focused proteomic analyses. The amount of NAMPT precipitated with anti-NAMPT monoclonal antibody was much higher in HCT116RFK866 than in the parental. Furthermore, in HCT116, but not in HCT116RFK866, NAMPT was revealed to interact with POTE ankyrin domain family member E and beta-actin. Thus, these results suggest that NAMPT usually interacts with the two partner proteins, and the H191R mutation may prevent the interactions, resulting in resistance to diverse NAMPT inhibitors.


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