CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer

Abstract

32 Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid 33 tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the 34 rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We 35 have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation 36 of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including 37 irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear 38 phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI 39 inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) 40 inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of 41 rabeprazole on CTDSP1 activity and its impact on colon cancer. Using HCT116 and 42 HT29, with high and low CTDSP1 expression respectively and a retrospective analysis 43 of patients receiving irinotecan with or without rabeprazole have indicated the effect of 44 CTDSP1 in irinotecan response. These results indicate that CTDSP1 promotes 45 sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance.46 To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI 47 for cancer patients treated with irinotecan. 49 Introduction50 Topoisomerase I (topoI) was identified as a specific target for camptothecin (CPT) and 51 its analogues like irinotecan [1]. Irinotecan is frequently used to treat colon, ovarian, 52 pancreatic, breast, and small cell lung cancer. TopoI reduces DNA supercoiling by cutting 53 and re-ligating DNA, and a controlled rotation between the cutting and re-ligation cycles 54 reduces the supercoiling. However, in the presence of irinotecan, the re-ligation cycle is 55 inhibited, and collision with a replication fork leads to a DNA double strand break (DNA-56 DSB) [2]. The topoI inhibitor camptothecin and its analogues (CPTs), like irinotecan and 57 topotecan are used extensively to treat various solid tumors. However, only 13-32% of 58 patients respond, and the mechanisms of resistance are not well-understood [3]. Classical 59 mechanisms of irinotecan resistance potentially involve an ATP-binding cassette (ABC) 60 transporter, ABCG2, which reduces intracellular drug accumulation [4][5][6]. Inhibition of 3 61 the ABCG2 drug efflux pump using sorafenib sensitizes both non-resistant cells and 62 resistant cells to irinotecan [7, 8]. Another proposed mechanism for irinotecan resistance 63 is topoI gene mutation[9]. However, DNA sequencing studies have failed to find topoI 64 gene mutations in cancer patients [10, 11]. Other mechanisms may include faster repair of 65 trapped topoI protein-linked DNA breaks, which is associated with perturbed histone 66 acetylation [8]. However, none of these studies have been conclusively shown to impart 67 cellular resistance to irinotecan. In response to irinotecan, topoI is ubiquitinated and 68 degraded by ubiquitin proteasoma...

Development of a tRNA-Derived Small RNA Prognostic Panel and Their Potential Functions in Osteosarcoma

“…Myosin light chain 3 (MYL3) encodes ventricular/cardiac isoform protein, which significantly decreased during fat accumulation in bovine skeletal muscle (20). Carboxy-Terminal Domain RNA Polymerase II Polypeptide A Small Phosphatase 1 (CTDSP1) is related to the drug resistance of colorectal cancers (21). Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 1 (CMTM1) was upregulated in testis and many tumor tissues, and also raised cell proliferation rates and resistance to tumor necrosis factor-a (TNF-a)-induced apoptosis (22).…”