RETRACTED ARTICLE: FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance

Intuyod, Kitti; Saavedra‐García, Paula; Zona, Stefania; Lai, Chun‐Fui; Jiramongkol, Yannasittha; Vaeteewoottacharn, Kulthida; Pairojkul, Chawalit; Yao, Shang J.; Yong, Jay-Sze; Trakansuebkul, Sasanan; Waraasawapati, Sakda; Luvira, Vor; Wongkham, Sopit; Pinlaor, Somchai; Lam, Eric W.‐F.

doi:10.1038/s41419-018-1235-0

Cited by 27 publications

(24 citation statements)

References 46 publications

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“…The prognosis of patients with recurrent or refractory OS is extremely poor, 2,11 highlighting the urgent need for more effective treatments of this grievous malignancy. In the present study, we found that FoxM1, a biomarker for a poor prognosis in many malignancies, [12][13][14][15] is upregulated in human OS tissues and MG-63 or HOS-MNNG cell lines. These data are consistent with previous reports showing that FoxM1 is overexpressed in a large set of human OS tissues.…”

Section: Discussionsupporting

confidence: 55%

<p>FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion</p>

Zhu¹,

Lu²,

Cao³

et al. 2020

CMAR

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Background: Osteosarcoma (OS) is a highly aggressive bone malignancy that is mostly diagnosed in children and young adults. Increasing evidence indicates that the transcription factor Forkhead Box M1 (FoxM1) plays a key role in the pathogenesis of various tumors. However, the function of FoxM1 in OS has not been clearly elucidated. Methods: In the present study, we first analyzed the expressions of FoxM1 in human OS and myositis ossificans (MO, included as a control) tissues by immunohistochemistry. To investigate the functional significance of FoxM1 in OS tumorigenesis, we examined the effects of FoxM1 downregulation in MG-63 and HOS-MNNG cells by either short hairpin RNA (shRNA)-mediated gene silencing or treatment with thiostrepton, a specific FoxM1 inhibitor. Results: FoxM1 was detected in 82.1% (55/67) of OS vs only 10% (2/20) of MO samples. High expressions of FoxM1 were also detected in three human OS cell lines (HOS-MNNG, MG-63, and U-2OS). FoxM1 downregulation significantly reduced MG-63 and HOS-MNNG cell proliferation, migration, and invasion as well as cell cycle arrest in the G2/M phase and increased apoptotic cell death. Conclusion: The present study demonstrated the critical role of FoxM1 in the pathogenesis of OS. Therefore, FoxM1 may serve as a potential therapeutic target for the treatment of OS.

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Section: Discussionsupporting

confidence: 55%

<p>FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion</p>

Zhu¹,

Lu²,

Cao³

et al. 2020

CMAR

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“…Next, we investigated loss-of-function (LOF) and gain-of-function (GOF) events of key enzymes of the pyrimidine metabolic pathways. TYMS is considered as the key therapeutic target for 5-FU and overexpression of its gene has been linked to 5-FU resistance in in vitro as well as in in vivo experiments (Watson et al 2010;Intuyod et al 2018). TYMS showed no LOF mutations in the breast and colorectal cohort, supporting the findings that TYMS is an essential gene (Blomen et al).…”

Section: Impact On Tumorigenesissupporting

confidence: 54%

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Christensen

Roest

Besselink

et al. 2019

Preprint

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5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures. The use of 5-Fluorouracil (5-FU) as an anticancer agent became routine practice soon after its primary synthesis in 1957, and remains essential in many chemotherapeutic regimens today (Longley, Harkin, and Johnston 2003). The fluoropyrimidines, especially 5-FU, capecitabine, tegafur and cytarabine, are currently the third most commonly used anticancer drug in the treatment of solid cancers, including colorectal and breast cancers, and over two million patients are estimated to be treated with fluoropyrimidines each year (Ezzeldin and Diasio 2004). Response rates of 5-FU as a single drug are 10-15%, but increase drastically (>50% response) when given in combination therapies with leucovorin together with oxaliplatin or irinotecan (i.e. FOLFOX and FOLFIRI, respectively) (de Gramont et al. 2000;Boige et al. 2010;Cameron, Gabra, and Leonard 1994).The antifolate property of fluoropyrimidines is thought to be the principal mechanism of action. Fluoropyrimidines are intracellularly converted into the antifolate 5-fluorodeoxyuridine monophosphate (5-FdUMP) that can form a covalent intermediate with the folate-dependent enzyme thymidylate synthase (TYMS) (Sommer and Santi 1974). Consequently, the formation of dTMP from dUMP is inhibited which results in an imbalance of the nucleotide pool that affects DNA synthesis, possibly through incorporation of uracil, and impairs genome replication, with negative consequences for rapidly dividing cells such as cancer cells. Moreover, it has been proposed that 5-fluorodeoxyuridine triphosphate (5-FdUTP) can be directly incorporated into genomic DNA as well (Pettersen et al. 2011;Huehls et al. 2016). Considering these properties, it is conceivable that fluoropyrimidines have mutagenic potential, although the mutational consequences of 5-FU tr...

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“…Western blot analysis: For western blot, whole-cell lysate of cells were prepared using RIPA buffer [20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na 2 EDTA, 1 mM EGTA, 1% NP-40, 1% sodium deoxycholate, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na3VO4 and 1 μg/mL leupeptin] as previously described 12 . The lysed samples were collected after centrifugation for 15 min at 12,000 × g, 4°C.…”

Section: Transwell-migration and Invasion Assaymentioning

confidence: 99%

“…Chromatin immunoprecipitation assay (ChIP): Chromatin immunoprecipitation was performed as previously described with minor modifications 12 . (See also Supplementary Materials and Methods).…”

Section: Transwell-migration and Invasion Assaymentioning

confidence: 99%

NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression

et al. 2020

Self Cite

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Estrogen-related receptor beta (ERRβ) is downregulated in breast cancer cells and its overexpression in breast cancer patients is positively correlated with an improved prognosis and prolonged relapse-free survival. Here, we unravelled a molecular mechanism for ERRβ downregulation in breast cancer. We found that ERRβ is a key substrate of the SCF complex and that NEDDylation can activate the Cullin subunits of the SCF complex to target ERRβ for degradation in breast cancer. Consistently, using in vitro and in vivo models, we demonstrated that MLN4924, a specific small molecule inhibitor of NEDDylation, can restore ERRβ expression and culminate in a reduction in cell proliferation and migration of breast cancer cells. We also showed that increased ERRβ expression promotes the upregulation of its target genes, including the tumour suppressors p21 Cip1/Waf1 and E-cadherin, involved in cell proliferation and migration arrest at the gene promoter level. Interestingly, this tumour suppressive role of ERRβ does not depend on the expression of ERα in breast cancer. Moreover, our data revealed that the ERRβ recruits the transcription co-activator p300 to its targeted gene promoters to upregulate their expression. Collectively, our work revealed that restoration of ERRβ expression using the NEDDylation inhibitor MLN4924 can be a novel and effective strategy for breast cancer treatment.

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RETRACTED ARTICLE: FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance

Cited by 27 publications

References 46 publications

<p>FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion</p>

<p>FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion</p>

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression

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