Pregnane X-receptor promotes stem cell-mediated colon cancer relapse

Planque, Chris; Rajabi, Fatemeh; Grillet, Fanny; Finetti, Pascal; Bertucci, François; Gironella, Meritxell; Lozano, Juan José; Beucher, Bertrand; Giraud, Julie; Garambois, Véronique; Vincent, Charles; Brown, Daniel V.; Caillo, Ludovic; Kantar, Jovana; Pèlegrin, André; Prudhomme, Michel; Ripoche, J.; Bourgaux, Jean François; Ginestier, Christophe; Castells, Antoni; Hollande, Frédéric; Pannequin, Julie; Pascussi, Jean‐Marc

doi:10.18632/oncotarget.10646

Cited by 38 publications

(52 citation statements)

References 56 publications

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“…BEL Attenuates RIF-Induced Resistance to SN-38. Previous studies have shown that elevated levels of PXR-mediated expression of drug-metabolizing enzymes and drug-efflux pumps in cancer cells contribute to increased resistance toward chemotherapy drugs (Pondugula and Mani, 2013;Planque et al, 2016;Pondugula et al, 2016). For instance, the activation of hPXR-mediated expression of drug-metabolizing enzymes and drug-efflux pumps decreases the sensitivity of human colon cancer cells, including LS174T cells, to several chemotherapy drugs such as SN-38 [the active metabolite of irinotecan (C 22 H 20 N 2 O 5 )] (Pondugula et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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Activation of pregnane X receptor (PXR) by clinical compounds during multidrug chemotherapy results in upregulation of the expression of PXR target genes, including cytochrome p450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1), leading to chemoresistance. It is possible to overcome the PXR‐mediated chemoresistance by downregulating the upregulated PXR target genes by inhibiting the activated PXR. However, a selective and less‐toxic PXR antagonist has yet to be developed. In this regard, a clinical anticancer drug, with selective PXR antagonistic activity at its less‐toxic concentrations, would be beneficial. We sought to determine whether belinostat, a clinically‐used histone deacetylase inhibitor, inhibits the PXR target gene expression at its clinically relevant plasma concentrations (< ~100 μM) in human hepatocytes (primary hepatocytes & hepatocells) and intestinal cells (LS174T colon cancer cells). Rifampicin, an agonist of human PXR, was used to activate PXR. Cell viability and CYQUANT cell proliferation assays were performed to determine cytotoxicity and cell proliferation, respectively. Quantitative RT‐PCR assays were conducted to study the gene expression. CYP3A4 p450‐Glo and Rhodamine‐123 intracellular accumulation assays were performed to determine the function of CYP3A4 and MDR1, respectively. Belinostat, at its unbound therapeutic plasma concentrations (< ~5 μM) did not affect the viability of LS174T cells and the hepatocytes. Belinostat (1 & 3 μM) not only inhibited rifampicin‐induced gene expression of CYP3A4 and MDR1, but also attenuated rifampicin‐induced activity of CYP3A4 and MDR1. However, belinostat alone did not affect CYP3A4 or MDR1 gene expression. These results suggest that belinostat does not affect the basal expression of PXR target genes but downregulates the upregulated PXR target genes by inhibiting the ligand‐activated PXR. Notably, belinostat, at its PXR inhibiting concentrations, decreased rifampicin‐induced proliferation of LS174T cells, suggesting that belinostat suppresses PXR‐mediated proliferation of the cancer cells. Interestingly, belinostat failed to inhibit rodent PXR agonist pregnenolone‐16 alpha‐carbonitrile (PCN)‐induced expression of CYP3A1 (the rat analog of human CYP3A4) in rat primary hepatocytes, suggesting that belinostat exhibits species‐specific inhibition of PXR at unbound plasma therapeutic concentrations. Taken together, these results are consistent with the conclusion that belinostat, at its less‐toxic and clinically relevant unbound plasma concentrations, inhibits the ligand‐activated human PXR target gene expression. Future studies will determine the mechanisms of belinostat inhibition of PXR, and belinostat sensitization of the cancer cells to chemotherapy drugs with PXR agonistic activity. Support or Funding Information The authors would like to thank Drs. Coleman, Schwartz, and Tao for sharing their research facilities. This work was supported by the Auburn University Research Initiative in Cancer Grant, Animal Health and Disease Research Grant...

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Section: Resultsmentioning

confidence: 99%

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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“…50,000 cells were subcutaneously injected into nude mice in Matrigel – DMEM (v : v). 50mg/kg 5-FU + 30mg/kg Irinotecan treatment (two i.p injection a week), was initiated once tumor reached 100 mm 3 [62]. These studies were approved by the ethics committee of the Languedoc Roussillon Region and carried out in compliance with the CNRS and INSERM ethical guidelines of animal experimentation (CEEA-LR-12051).…”

Section: Methodsmentioning

confidence: 99%

FTO-mediated cytoplasmic m⁶A_mdemethylation adjusts stem-like properties in colorectal cancer cell

Relier

Ripoll

Guillorit

et al. 2020

Preprint

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20Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display 21 inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence 22 establishing a link between deregulation of epitranscriptome-related players and tumorigenic 23 process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC 24 properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and 25 obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m 6 Am (N 6 ,2'-26 O-dimethyladenosine) demethylase activity. While m 6 Am is strategically located next to the m 7 G-27 mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low 28 FTO expression in patient-derived cell lines elevates m 6 Am level in mRNA which results in enhanced 29 in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m 6 Am methyltransferase, 30 PCIF1/CAPAM, partially reverses this phenotype. FTO-mediated regulation of m 6 Am marking 31 constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome 32 remodeling, but could fine-tune translation efficiency of selected m 6 Am marked transcripts. 33 Altogether, our findings bring to light the first biological function of the m 6 Am modification and its 34 potential adverse consequences for colorectal cancer management. 35 36 Despite significant advances in diagnosis and therapy, colorectal cancer (CRC) remains a major 37 cause of mortality and morbidity worldwide. CRC survival is highly dependent upon early diagnosis. 38 Patients with localized cancer exhibit 70 to 90% 5-year survival. Survival from metastatic cancer 39 plummets to 10%. Metastasis is a multistep process encompassing local infiltration of tumor cells into 40 adjacent tissues, transendothelial migration into vessels, survival in the circulatory system, 41 extravasation, and colonization of secondary organs [1]. This process entails constant reprogramming 42 of gene expression to enable tumor adaptation in different environments, a peculiar trait of cancer 43 stem cells (CSCs). CSC constitute a minor subpopulation of tumor cells endowed with self-renewal and 44 multi-lineage differentiation capacity [2]. The most clinically relevant trait of CSCs is their ability to 45 metastasize and escape from standard chemotherapy [3]. Understanding the molecular mechanisms 46 that participate to the CSC phenotype is critical to designing improved cancer therapeutics. 47 Discovered several decades ago [12-16], the function of m 6 A remained obscure until the identification 55 of the first m 6 A demethylase, the fat mass and obesity-associated protein (FTO) [17]. The marriage of 56 immunochemical approaches with next-generation sequencing (NGS) technologies revealed the 57 unique topology of m 6 A distribution along mRNA. m 6 A is a dynamic reversible chemical modification 58 catalyzed by a protein complex consisting of the methyl...

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“…by regulating a network of downstream genes involved in self-renewal and chemoresistance [75]. PXR expression is associated with CSC enrichment, after cell sorting of cancer cells using ALDH activity to identify CSCs and after spheroid passaging.…”

Section: Planque Et Al Have Recently Demonstrated That Pxr Is a Potementioning

confidence: 99%

“…PXR expression is associated with CSC enrichment, after cell sorting of cancer cells using ALDH activity to identify CSCs and after spheroid passaging. In addition, expression of CSC markers and self-renewal are increased in CRC cells with enhanced PXR transcriptional activity [75]. PXR expression in intestinal CSCs is also associated with tumor aggressiveness and chemoresistance [76].…”

Section: Planque Et Al Have Recently Demonstrated That Pxr Is a Potementioning

confidence: 99%

See 1 more Smart Citation

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

Gleizes¹,

Cavaillès²,

Lapierre³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Colorectal cancer (CRC) is one of the most frequent cancers worldwide. Current treatments include surgery and chemotherapy, but disease recurrence occurs frequently. The continuous renewal of intestinal epithelium relies on the presence of intestinal stem cells that are also at the origin of CRC and contribute to therapy resistance and metastatic dissemination. Several nuclear signaling pathways and transcription factors regulate both intestinal cell homeostasis and tumorigenesis. However, the transcriptional events that govern the emergence of aggressive therapy-resistant cancer stem cells are still poorly defined. This review summarizes the relevance of transcription factors in intestinal stem cell biology and their involvement in colon cancer development and drug resistance.

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Pregnane X-receptor promotes stem cell-mediated colon cancer relapse

Cited by 38 publications

References 56 publications

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

FTO-mediated cytoplasmic m⁶A_mdemethylation adjusts stem-like properties in colorectal cancer cell

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

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Pregnane X-receptor promotes stem cell-mediated colon cancer relapse

Cited by 38 publications

References 56 publications

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

FTO-mediated cytoplasmic m6Amdemethylation adjusts stem-like properties in colorectal cancer cell

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

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FTO-mediated cytoplasmic m⁶A_mdemethylation adjusts stem-like properties in colorectal cancer cell