MCCC2 overexpression predicts poorer prognosis and promotes cell proliferation in colorectal cancer

Dai, Wei; Feng, Huiying; Lee, Dongwon

doi:10.1016/j.yexmp.2020.104428

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…Even though the number of analyzed tumor samples is limited, these results suggest that leucine can be a metabolic substrate for brain tumor cells. The expression of the MCC has also been confirmed previously in various breast [30], prostate [29,63], colorectal [31], and hepatocellular [32] tumors. Furthermore, several studies revealed novel signaling and regulatory functions intervened by the smaller subunit of MCC, MCCC2, in cancer cells [29,32].…”

Section: Discussionsupporting

confidence: 70%

“…In this respect, MCCC2 can affect the intracellular signaling cascade facilitated by promoting the activation of ERK in the cytosol of human hepatocarcinoma cells [32] or regulating the GLUD1-P38 MAPK signaling pathway in [29] prostate cancer cells. MCCC2 also exerts its regulatory function on cell proliferation and migration capabilities [29][30][31][32]. Presently, it remains unknown to which extent metabolic and regulatory roles of MCC in brain tumor-forming cells are critical.…”

Section: Discussionmentioning

confidence: 99%

“…The mutations in MCC subunit genes lead to MCC deficiency (MIM# 210200 and MIM# 210210), an autosomal recessive disorder with a very variable phenotype [28]. The increased expression of MCC promotes proliferation of prostate [29], breast [30], and colorectal cancer cells [31] and is critical for the oncogenesis of hepatocellular carcinoma [32].…”

Section: Introductionmentioning

confidence: 99%

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Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Gondáš

Trančiková

Baranovičová

et al. 2022

Cancers

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Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Gondáš

Trančiková

Baranovičová

et al. 2022

Cancers

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“…During CRC progression, many protein-coding genes act as oncogenes, such as myeloid differentiation factor 88 (MyD88) ( 24 ) ubiquitin‑like modifieractivating enzyme 2 (UBA2) ( 25 ). EIF3H ( 26 ), MCCC2 ( 27 ), SLC38A1 ( 28 ) and many protein-coding genes function as tumor suppressors, such as FH535 ( 29 ), ubiquitin-specific protease 44 (USP44) ( 30 ), phosphatase of regenerating liver-3 (PRL-3) ( 31 ), CPEB3 ( 32 ), etc. Even so, the investigation of CRC is still challenging, and many relevant questions remain to be answered.…”

Section: Discussionmentioning

confidence: 99%

Nestin protein affects the maintenance of stem characteristics of colorectal cancer cells based on p53 dependent pathway

Li¹,

Wu²,

Yu³

et al. 2022

J Gastrointest Oncol

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Background: Colorectal cancer (CRC) is a tumor with high incidence and poor prognosis. An increasing number of studies have shown that intermediate filament proteins, such as nestin, participate in the regulation of tumor progression. However, the mechanism related to CRC is complex, and the role and underlying mechanism of nestin have not been elucidated in CRC.Methods: We conducted quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot analyses to examine the mRNA and protein levels in CRC and normal tissues. siRNAs targeting Nestin were transfected into CRC cells and then cell counting kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), sphere formation, and transwell analyses were used to assess the role of nestin in the proliferation, stem activity, migration, and invasive ability of CRC cells. Afterwards, nestin was overexpressed in CRC cells and P53 was overexpressed as a rescue group. CCK-8, EdU dyeing, sphere formation, and transwell assay was used to evaluated the role of Nestin/p53 axis in CRC cells.Results: We found high nestin expression and low p53 expression in CRC tissues and cells. Functionally, silencing of nestin suppressed the multiplication, stemness, and metastatic ability of Caco-2 and RKO cells.Encouragingly, rescue experiments suggested that overexpression of p53 partly restored the impacts of nestin overexpression on the viability, proliferation, and metastatic ability of CRC cells. Conclusions:We confirmed that nestin and p53 play a functional role in the progression of CRC, and they may act as potential therapeutic targets for CRC treatment.

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“…Documented in many species (Diez et al, 1994; Gallardo et al, 2001; Höschle et al, 2005), MCC shares high cross-species sequence homology (Figure S1). In humans, upregulated MCC expression often correlates with various cancers (Chen et al, 2021; Dai et al, 2020; Gondáš et al, 2022; He et al, 2020; Liu et al, 2019). On the other hand, MCC deficiency, one of the most common metabolic disorders in newborns (Lee and Hong, 2014), may cause vomiting, seizures, and other neurological abnormalities (Grünert et al, 2012; Kim et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Discovery, Structure, and Function of Filamentous 3-Methylcrotonyl-CoA Carboxylase

Lee

Liu

et al. 2022

Preprint

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3-methylcrotonyl-CoA carboxylase (MCC) is a biotin-dependent enzyme necessary for leucine catabolism in most organisms. While the crystal structure of recombinant bacterial MCC has been characterized, the structure and potential polymerization of native MCC remain elusive. Here, we discovered that native MCC from Leishmania tarentolae (LtMCC) forms filaments and determined its structure at near-atomic resolution using cryoEM. α6β6 LtMCC dodecamers assemble in a twisted-stacks architecture, manifesting as supramolecular rods extending up to approximately 400 nanometers. LtMCCs in filaments bind biotin but are not covalently biotinylated and lack coenzyme A. Filaments elongate by stacking α6β6 LtMCCs onto the exterior α-trimer of the terminal α6β6 dodecamer. This stacking immobilizes the biotin carboxylase domains, sequestering the enzyme in an inactive state within the mitochondrial matrix. Our results support a new model for LtMCC catalysis, termed the dual-swinging-domains model, and cast new light on the functional significance of polymerization in the carboxylase superfamily and beyond.

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MCCC2 overexpression predicts poorer prognosis and promotes cell proliferation in colorectal cancer

Cited by 8 publications

References 26 publications

Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Nestin protein affects the maintenance of stem characteristics of colorectal cancer cells based on p53 dependent pathway

Discovery, Structure, and Function of Filamentous 3-Methylcrotonyl-CoA Carboxylase

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