<scp>BRCA</scp>/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

Nakashima, Shinsuke; Kobayashi, Shogo; Nagano, Hiroaki; Tomokuni, Akira; Tomimaru, Yoshito; Asaoka, Tadafumi; Hama, Naoki; Wada, Hiroshi; Kikuchi, Kôichi; Marubashi, Shigeru; Eguchi, Hidetoshi; Doki, Yuichiro; Mori, Masaki

doi:10.1111/cas.12652

Cited by 20 publications

(5 citation statements)

References 52 publications

(120 reference statements)

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“…The tumor suppressor BRCA gene plays a key role in the repair of fatal DNA double strand breaks and is involved in the development of several tumors [46]. Interestingly, it was demonstrated that the BRCA/FA pathway genes and proteins were upregulated in a GEM resistant model of CCA [47].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine

Varamo

Peraldo-Neia

Ostano

et al. 2019

Cancers

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Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. Late diagnosis and chemotherapy resistance contribute to the scarce outfit and poor survival. Resistance mechanisms are still poorly understood. Here, we established a Gemcitabine (GEM) resistant model, the MT-CHC01R1.5 cell line, obtained by a GEM gradual exposure (up to 1.5 µM) of the sensitive counterpart, MT-CHC01. GEM resistance was irreversible, even at high doses. The in vitro and in vivo growth was slower than MT-CHC01, and no differences were highlighted in terms of migration and invasion. Drug prediction analysis suggested that Paclitaxel and Doxycycline might overcome GEM resistance. Indeed, in vitro MT-CHC01R1.5 growth was reduced by Paclitaxel and Doxycycline. Importantly, Doxycycline pretreatment at very low doses restored GEM sensitivity. To assess molecular mechanisms underlying the acquisition of GEM resistance, a detailed analysis of the transcriptome in MT-CHC01R1.5 cells versus the corresponding parental counterpart was performed. Transcriptomic analysis showed that most up-regulated genes were involved in cell cycle regulation and in the DNA related process, while most down-regulated genes were involved in the response to stimuli, xenobiotic metabolism, and angiogenesis. Furthermore, additional panels of drug resistance and epithelial to mesenchymal transition genes (n = 168) were tested by qRT-PCR and the expression of 20 genes was affected. Next, based on a comparison between qRT-PCR and microarray data, a list of up-regulated genes in MT-CHC01R1.5 was selected and further confirmed in a primary cell culture obtained from an ICC patient resistant to GEM. In conclusion, we characterized a new GEM resistance ICC model that could be exploited either to study alternative mechanisms of resistance or to explore new therapies.

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Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine

Varamo

Peraldo-Neia

Ostano

et al. 2019

Cancers

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“…Therefore, it may be possible to overcome resistance to ICL-inducing therapies (e.g. cisplatin and MMC) by modulating AMPK activity in cancers that highly express FANC proteins in the FA/BRCA pathway [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks

et al. 2016

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Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments. Additionally, we showed that AMPKα interacted with FANCA, another component of the FA nuclear core complex. AMPKα knockdown in U2OS cells decreased FANCD2 monoubiquitination and nuclear foci formation upon mitomycin C-induced ICLs. Furthermore, AMPKα knockdown enhanced cellular sensitivity to MMC. MMC treatment resulted in an increase in AMPKα phosphorylation/activation, indicating AMPK is involved in the cellular response to ICLs. FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway. Our data suggest AMPK is involved in the activation of the FA/BRCA pathway.

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“…Resistance to anti-tumor treatments is a hallmark of cancer and CSCs and caused by up-regulation of genes responsible for drug efflux and DNA repair[ 4 ]. Nakashima and colleagues demonstrated an increase of proportion of CD24+/CD44+ cells in gemcitabine-resistant BTC cells and showed that genes of the BRCA/Fanconi repair pathway was over-expressed here, thus connecting the observed chemoresistance in these CSCs with a particular repair pathway[ 45 ]. Expression of the drug efflux pump ABCG2 is another mechanism of cells to gain therapeutic resistance and also an established CSC marker[ 46 ].…”

Section: Cancer Stem Cell Markers In Biliary Tract Cancer - An Overvimentioning

confidence: 99%

Biliary tract cancer stem cells - translational options and challenges

Mayr

Ocker

Ritter

et al. 2017

WJG

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Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells - the cancer stem cells - possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

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BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

Cited by 20 publications

References 52 publications

Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine

Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine

AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks

Biliary tract cancer stem cells - translational options and challenges

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