Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway

Ando, Koji; Shah, Ankur K.; Sachdev, Vibhu; Kleinstiver, Benjamin P.; Taylor-Parker, Julian; Welch, Moira M.; Hu, Yiheng; Salgia, Ravi; White, Forest M.; Parvin, Jeffrey D.; Ozonoff, Al; Rameh, Lucia E.; Joung, J. Keith; Bharti, Ajit

doi:10.18632/oncotarget.16376

Cited by 20 publications

(26 citation statements)

References 52 publications

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“…CPT-induced TOP1cc also induce DSBs, which activate DNA-PK that reduces the induction of RND1 . DNA-PK could reduce the induction of RND1 by promoting TOP1 proteolysis as previously reported 22 , 52 . Albeit in a lesser extent, ATM, which can activate DNA-PK 22 , also reduces the induction of RND1 .…”

Section: Discussionsupporting

confidence: 74%

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PARP-1-dependent RND1 transcription induced by topoisomerase I cleavage complexes confers cellular resistance to camptothecin

et al. 2018

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RHO GTPases regulate essential functions such as the organization of the actin cytoskeleton. The classic members cycle between an active GTP-bound and an inactive GDP-bound conformation whereas atypical members are predominantly GTP-bound. Besides their well-established role, the classic RHO GTPases RHOB and RAC1, are rapidly induced and/or activated by genotoxic stress and contribute to the DNA damage response. Here we used camptothecin, a selective topoisomerase I (TOP1) inhibitor that stabilizes TOP1 cleavage complexes (TOP1cc), to search for other potential early DNA damage-inducible RHO GTPase genes. We identified that an atypical RHO GTPase, RND1, is rapidly induced by camptothecin. RND1 induction is closely associated with the presence of TOP1cc induced by camptothecin or by DNA lesions that elevate TOP1cc levels such as UV and hydrogen peroxide. We further demonstrated that camptothecin increases RND1 gene transcription and mRNA stability. Camptothecin also increases poly(ADP-ribose) polymerase 1 (PARP-1) activity, whose inhibition reduces RND1 transcription. In addition, overexpression of RND1 increases PARP-1, suggesting a cross-talk between PARP-1 and RND1. Finally, RND1 protects cells against camptothecin-induced apoptosis, and hence favors cellular resistance to camptothecin. Together, these findings highlight RND1 as an atypical RHO GTPase early induced by TOP1cc, and show that the TOP1cc-PARP-1-RND1 pathway protects cells against apoptosis induced by camptothecin.

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Section: Discussionsupporting

confidence: 74%

“…TOP1cc also activates a PARP-1-RND1 pathway that counteracts the induction of apoptosis [2]. DNA-PK-dependent DSB signaling prevents RND1 induction, possibly by promoting TOP1cc removal 22 , 52 [3]. …”

Section: Discussionmentioning

confidence: 99%

PARP-1-dependent RND1 transcription induced by topoisomerase I cleavage complexes confers cellular resistance to camptothecin

et al. 2018

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“…We have previously reported that topo I is phosphorylated by DNA-PKcs at serine-10, and the resulting phosphoprotein (topoI-pS10) is efficiently ubiquitinated and targeted for rapid proteasomal degradation[3]. Protein phosphatases have been shown to interact with DNA-PKcs and could serve as upstream regulators of DNA-PKcs.…”

Section: Resultsmentioning

confidence: 99%

“…Our siRNA library screen of nuclear phosphatase identified PTEN and CTDSP1 as two phosphatases that significantly enhance the CPT induced topoI degradation. Importantly, we have demonstrated that PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and irinotecan resistance[3]. We asked if CTDSP1 also dephosphorylates DNA-PKcs, and is the upstream regulator of CPT induced topoI degradation.…”

Section: Discussionmentioning

confidence: 99%

“…The topoI inhibitor camptothecin and its analogues (CPTs), like irinotecan and topotecan are used extensively to treat various solid tumors. However, only 13-32% of patients respond, and the mechanisms of resistance are not well-understood[3]. Classical mechanisms of irinotecan resistance potentially involve an ATP-binding cassette (ABC) transporter, ABCG2, which reduces intracellular drug accumulation [4–6].…”

Section: Introductionmentioning

confidence: 99%

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

Matsuoka

Ando

Swayze

et al. 2020

Preprint

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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...

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Natural Products as Cytotoxic Agents

Pullman,

León,

Cutler

2021

Burger's Medicinal Chemistry and Drug Discovery

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Nature has proved to be a wellspring of important antineoplastic agents. In recent years, there has been a resurgence in the study of natural products with an emphasis on the discovery of novel therapeutic agents. New technologies and approaches such as high‐throughput screening, parallel synthesis, and other programs has facilitated this increased interest in natural products research. The scientific literature indicates that natural sources not previously considered as bioactive have in fact, become potential valuable treasure troves of novel chemical structures. For example, marine products from diverse sources such as thermal vents, sponges, terrestrial thermal vents, glacial cryogenic organisms, and xerophytic and endophytic organisms now give rise to a vast assortment of microorganisms. Additionally, the study of the biosynthetic machineries and biochemical process in microorganism has enhanced the research of cryptic natural products, fueling the search for natural products in the treatment of cancer. It comes as no surprise that nature biosynthesizes chemical compounds that chemists have not considered even in their imaginations. Although this article provides a few of these examples, it is certain that more will be present in the literature as the intellectual property in these discoveries are protected.

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Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway

Cited by 20 publications

References 52 publications

PARP-1-dependent RND1 transcription induced by topoisomerase I cleavage complexes confers cellular resistance to camptothecin

PARP-1-dependent RND1 transcription induced by topoisomerase I cleavage complexes confers cellular resistance to camptothecin

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

Natural Products as Cytotoxic Agents

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