TY - JOUR
T1 - CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer
AU - Matsuoka, Hiroya
AU - Ando, Koji
AU - Swayze, Emma J.
AU - Unan, Elizabeth C.
AU - Mathew, Joseph
AU - Hu, Quingjiang
AU - Tsuda, Yasuo
AU - Nakashima, Yuichiro
AU - Saeki, Hiroshi
AU - Oki, Eiji
AU - Bharti, Ajit K.
AU - Mori, Masaki
N1 - Publisher Copyright:
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/7
Y1 - 2020/1/7
N2 - Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on colon cancer. Using HCT116 and HT29, with high and low CTDSP1 expression respectively and a retrospective analysis of patients receiving irinotecan with or without rabeprazole have indicated the effect of CTDSP1 in irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.
AB - Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on colon cancer. Using HCT116 and HT29, with high and low CTDSP1 expression respectively and a retrospective analysis of patients receiving irinotecan with or without rabeprazole have indicated the effect of CTDSP1 in irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.
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U2 - 10.1101/2020.01.07.897355
DO - 10.1101/2020.01.07.897355
M3 - Article
AN - SCOPUS:85094302508
JO - Quaternary International
JF - Quaternary International
SN - 1040-6182
ER -