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Cited by 242Dietary Effects on HealthCancer, Lipids, and MetabolismCancer, Hypoxia, and Metabolism

RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

Open access
Weng, Mei-lin, Chen, Wan-kun, Chen, Xiang-yuan, Lu, Hong, Sun, Zhi-rong, Yu, Qi, Sun, Peng-fei, Xu, Ya-jun +8 more·2020·Nature Communications
DOI 10.1038/s41467-020-15795-8PMC PMC7170903
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Abstract

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

AI snapshot

Written from the paper’s full text.

TL;DR

This retracted article reports that fasting upregulates FDFT1, which suppresses aerobic glycolysis and proliferation in colorectal cancer via negative regulation of AKT/mTOR/HIF1α signaling. FDFT1 downregulation is associated with malignant progression and poor prognosis, and mTOR inhibition synergized with fasting in mouse models.

Key findings

  • Fasting inhibited CRC cell proliferation and glycolysis: it reduced glucose uptake and lactate production, decreased ECAR, increased OCR, and downregulated GLUT1, HK2, LDHA, PGK1, and GPI. In CT26 xenografts, fasting-mimicking diet attenuated tumor growth, with lower final tumor weights and volumes (n = 5; P = 0.001 and P = 0.0292) and reduced 18F-FDG SUVmax ratio (n = 3; P = 0.0459).
  • FDFT1 was upregulated by fasting and downregulated in CRC. FDFT1 was lower in 19/23 tumor tissues and higher in 18/23 adjacent noncancerous tissues (n = 23; P = 0.0004); FDFT1 mRNA was lower in 81 CRC tissues than matched noncancerous tissues (both P < 0.0001). High FDFT1 predicted better prognosis in FUSCC (39 high vs 42 low; P = 0.0238) and TCGA (P = 0.018), and lower FDFT1 correlated with higher TNM stage (P = 1.91 × 10−5).
  • FDFT1 overexpression inhibited CRC proliferation and invasion, induced G0/G1 arrest and apoptosis, while FDFT1 knockdown promoted proliferation and invasion; FDFT1 knockdown reversed fasting-mediated inhibition in vitro and in vivo.
  • FDFT1 negatively regulated AKT/mTOR/HIF1α signaling; mTOR silencing reduced proliferation and glycolysis. Rapamycin plus fasting-mimicking diet inhibited CRC and improved mouse survival (log-rank P = 0.0049 for FMD, P = 0.0058 for rapamycin, P = 0.00069 for combination).

Methods

  • In vitro studies used CRC cell lines CT26, SW620, HCT116, HT29, and NCM460; fasting was mimicked with glucose-free DMEM plus 0.5 g/L glucose and 1% FBS for 24 or 48 h. Lentiviral FDFT1/SREBP2 overexpression and knockdown, mTOR siRNA, CCK8, EdU, colony formation, Transwell, flow cytometry, glucose/lactate assays, Seahorse ECAR/OCR, qRT-PCR, western blotting, and iTRAQ proteomics were used.
  • In vivo studies subcutaneously injected CT26 or modified CT26 cells into BALB/c mice, used fasting-mimicking diet cycles, rapamycin 1 mg/kg/d, 18F-FDG microPET/CT imaging, and IHC.
  • Human analyses included 81 CRC patients from FUSCC (2012–2013) with paired noncancerous tissues, plus TCGA/GEO/GEPIA datasets; statistics included two-sided t tests, ANOVA, chi-square tests, Kaplan–Meier analysis, and log-rank tests.

Limitations

  • The paper states that the mechanism by which FDFT1 affects mTOR needs further exploration, that clinical application of FDFT1 will be challenging, and that other pathways may mediate FDFT1 effects on tumor growth.
  • Evident from the text: the article is labeled “RETRACTED ARTICLE” in the title, so the findings should be treated with caution; the provided text does not give the retraction reason.
  • Evident from the text: animal experiments often used small group sizes (e.g., n = 3–5), and human evidence is retrospective/cohort or database-based rather than from an interventional fasting trial.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-020-15795-8This paper is marked retracted.

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    FDFT1 downregulation is correlated with malignant progression and poor prognosis in CRC.

    “In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC.”
    • Also stated in: § FDFT1 is upregulated by fasting and correlates with prognosis in CRC · hedged
      “Altogether, these results indicated that FDFT1 was downregulated in CRC tissues, and was correlated with malignant progression and poor prognosis in patients with CRC.”
    Quote in the paperSubstantial claim
  • Findingown data

    High FDFT1 expression in CRC is associated with better prognosis in TCGA data sets.

    “Clinically, high FDFT1 expression in CRC is associated with better prognosis in The Cancer Genome Atlas (TCGA) data sets.”
    • Also stated in: § FDFT1 is upregulated by fasting and correlates with prognosis in CRC · hedged
      “The survival analysis of the data from the TCGA data set indicated that high FDFT1 expression was associated with better prognosis (P = 0.018, log-rank test) (Fig. 2m).”
    • Also stated in: § Discussion · plain
      “Clinically, high FDFT1 expression in CRC is associated with better prognosis in The Cancer Genome Atlas (TCGA) data sets.”
    Quote in the paperSubstantial claim
  • Findingown data

    Fasting upregulates FDFT1 expression during the inhibition of CRC cell aerobic glycolysis and proliferation.

    “We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation.”
    • Also stated in: § FDFT1 is upregulated by fasting and correlates with prognosis in CRC · plain
      “Our results thus showed that fasting upregulates the expression of FDFT1 in CRC.”
    Quote in the paperSubstantial claim
  • Findingown data

    FDFT1 overexpression and fasting for 48 h inhibited CT26 cell proliferation as measured by a CCK8 assay.

    “FDFT1 overexpression and fasting for 48 h inhibited CT26 cell proliferation as measured by a CCK8 assay.”
    Quote in the paperSubstantial claim
  • Findingown data

    FDFT1 knockdown combined with fasting abrogated the fasting inhibition of CRC cell proliferation in an EdU assay.

    “an EdU assay showed that FDFT1 knockdown combined with fasting abrogated the fasting inhibition of CRC cell proliferation”
    Quote in the paperSubstantial claim
  • May combine two claims. 38
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Fasting and FDFT1 overexpression increased the protein level of FDFT1 in CRC cells.

    “Western blotting indicated that fasting and FDFT1 overexpression increased the protein level of FDFT1 in CRC cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FDFT1 overexpression induced G0/G1 phase cell cycle arrest and apoptosis.

    “In addition, FDFT1 overexpression induced G0/G1 phase cell cycle arrest and apoptosis (Supplementary Figs. 13b, c and 15i, j)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The top significantly enriched biological process and KEGG pathway were the "Cholesterol biosynthetic process" and the "Steroid biosynthesis pathway", respectively.

    “Via the Database for Annotation, Visualization and Integrated Discovery (DAVID, https://david.ncifcrf.gov/), the top significantly enriched biological process and KEGG pathway were the “Cholesterol biosynthetic process” and the “Steroid biosynthesis pathway”, respectively (Supplementary Fig. 10a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SREBP2 overexpression decreased colony-formation capacity, whereas SREBP2 knockdown increased colony-formation capacity.

    “We also performed a colony-formation assay when overexpressing or knocking down SREBP2, and the results showed that SREBP2 overexpression decreased, whereas SREBP2 knockdown increased colony-formation capacity (Supplementary Fig. 12f, g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both FMD and FDFT1 overexpression inhibited tumor growth in mice.

    “Both the FMD and FDFT1 overexpression inhibited tumor growth in the mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of SREBP2 upregulated FDFT1 and vice versa, and the overexpression of SREBP2 was more pronounced during fasting simulation.

    “Then, we examined the protein and mRNA levels of FDFT1 when overexpressing or knocking down SREBP2, and found that overexpression of SREBP2 upregulated FDFT1 and vice versa, moreover, the overexpression of SREBP2 was more pronounced during fasting simulation (Supplementary Fig. 12h, i).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FDFT1 knockdown induced S phase cell cycle arrest and attenuated apoptosis.

    “whereas FDFT1 knockdown induced S phase cell cycle arrest and attenuated apoptosis (Supplementary Figs. 14b, c and 16i, j).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The expression of FDFT1 was downregulated in most tumor tissues (19/23) but upregulated in most adjacent noncancerous tissues (18/23).

    “The expression of FDFT1 was downregulated and lower in most of the tumor tissues (19/23), but upregulated in most of the adjacent noncancerous tissues (18/23) (Fig. 2f, g).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    iTRAQ proteomics showed 111 differentially upregulated genes and 168 differentially downregulated genes between the control and fasting groups.

    “The heatmap showed 111 differentially upregulated genes and 168 differentially downregulated genes between the control and fasting groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fasting 48 h and FDFT1 overexpression increased the protein level of FDFT1 in CRC cells.

    “fasting 48 h and FDFT1 overexpression increased the protein level of FDFT1 in CRC cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most enriched biological pathway and biological process in the GSE60653 dataset were the "Cholesterol biosynthesis" pathway and the "Energy pathway" and "Metabolism" processes.

    “Surprisingly, the most enriched biological pathway and biological process were the “Cholesterol biosynthesis” pathway and the “Energy pathway” and “Metabolism” processes (Supplementary Fig. 9c–f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mTOR protein levels decreased following FDFT1 overexpression, but increased following FDFT1 knockdown.

    “mTOR protein levels decreased following FDFT1 overexpression, but increased following FDFT1 knockdown”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In FDFT1 knockdown, ECAR was increased, but OCR was decreased.

    “in FDFT1 knockdown, ECAR was increased, but OCR was decreased”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of FDFT1 and fasting reduced glycolysis and total cholesterol levels.

    “overexpression of FDFT1 and fasting reduced glycolysis and total cholesterol levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    An mTOR activator prevents an increase in FDFT1 protein levels in FDFT1 overexpression cells, identifying an inverse relationship between FDFT1 and mTOR.

    “an mTOR activator prevents an increase in FDFT1 protein levels in FDFT1 overexpression cells, identifying an inverse relationship between FDFT1 and mTOR”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cells overexpressing FDFT1, ECAR was reduced, but OCR was increased.

    “in cells overexpressing FDFT1, ECAR was reduced, but OCR was increased”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Silencing mTOR decreased ECAR but increased OCR of CT26 and SW620 cells.

    “the silencing of mTOR decreased the ECAR, but increased the OCR of CT26 and SW620 cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fasting and rapamycin synergize in delaying CRC progression, improving survival, and upregulating FDFT1.

    “fasting and rapamycin synergize in delaying CRC progression, improving survival, and upregulating FDFT1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fasting upregulates the Steroid biosynthesis pathway, and FDFT1 was dramatically upregulated.

    “fasting upregulates the “Steroid biosynthesis” pathway, and that FDFT1 was dramatically upregulated”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both FMD and 1 mg/kg dose of rapamycin can robustly inhibit proliferation of CRC and drastically improve survival.

    “both FMD and 1 mg/kg dose of rapamycin can robustly inhibit the proliferation of CRC and drastically improve survival”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fasting dramatically inhibited 18F-FDG uptake and attenuated tumor growth in xenograft model.

    “Fasting dramatically inhibited 18F-FDG uptake and attenuated tumor growth in this xenograft model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fasting and FDFT1 overexpression reduced total cholesterol production in CRC cell lines.

    “Our study showed that fasting and FDFT1 overexpression reduced the total cholesterol production in CRC cell lines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Increased FDFT1 transcription is associated with increased invasion in prostate cancer.

    “Although increased FDFT1 transcription is associated with increased invasion in prostate cancer, the exact role of FDFT1 in CRC progression has not been investigated35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Fukuma, Y. et al. Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer. Prostate Cancer Prostatic Dis. 15, 339–345 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    FDFT1 is a key downstream target of the fasting response and is involved in CRC cell glucose metabolism.

    “These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism.”
    • Also stated in: § Introduction · hedged
      “Overall, our results indicate that FDFT1 is a key downstream target of the fasting response and involve in CRC cell glucose metabolism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fasting is thought to work at least in part through the inhibition of insulin/IGF-1/mTORC1 signaling.

    “On the molecular level, fasting is not well understood but based on the data from studies on fasting-mediated longevity and stress resistance, it is thought to work at least in part through the inhibition of insulin/IGF-1/mTORC1 signaling15–18.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Efeyan, A., Comb, W. C. & Sabatini, D. M. Nutrient-sensing mechanisms and pathways. Nature 517, 302–310 (2015). source

      Not checked in the free run.

    • cites [16] Buono, R. & Longo, V. D. Starvation, stress resistance, and cancer. Trends Endocrinol. Metab. 29, 271–280 (2018). source

      Not checked in the free run.

    • cites [17] Tulsian, R., Velingkaar, N. & Kondratov, R. Caloric restriction effects on liver mTOR signaling are time-of-day dependent. Aging 10, 1640–1648 (2018). source

      Not checked in the free run.

    • cites [18] Blagosklonny, M. V. Fasting and rapamycin: diabetes versus benevolent glucose intolerance. Cell Death Dis. 10, 607 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FDFT1 encodes a membrane-associated enzyme acting at a branch point in the mevalonate pathway.

    “Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) encodes a membrane-associated enzyme acting at a branch point in the mevalonate pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Brusselmans, K. et al. Squalene synthase, a determinant of Raft-associated cholesterol and modulator of cancer cell proliferation. J. Biol. Chem. 282, 18777–18785 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The FDFT1-encoded protein is the first enzyme in cholesterol biosynthesis and catalyzes the dimerization of two molecules of farnesyl diphosphate via a two-step reaction to form squalene.

    “The encoded protein is the first enzyme in cholesterol biosynthesis and catalyzes the dimerization of two molecules of farnesyl diphosphate via a two-step reaction to form squalene32, which plays an important role in cholesterol biosynthesis33,34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Brusselmans, K. et al. Squalene synthase, a determinant of Raft-associated cholesterol and modulator of cancer cell proliferation. J. Biol. Chem. 282, 18777–18785 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Fasting impairs glycolysis and inhibits proliferation in CRC.

    “Taken together, these results suggested that fasting impairs glycolysis and inhibits proliferation in CRC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FDFT1 is downregulated in CRC tissues and cell lines.

    “Therefore, FDFT1 is downregulated in CRC tissues and cell lines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FDFT1 was downregulated in CRC tissues and was correlated with malignant progression and poor prognosis in patients with CRC.

    “Altogether, these results indicated that FDFT1 was downregulated in CRC tissues, and was correlated with malignant progression and poor prognosis in patients with CRC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FDFT1 overexpression inhibited cell proliferation and induced G0/G1 phase cell cycle arrest and apoptosis, while FDFT1 knockdown promoted cell proliferation, induced S phase cell cycle arrest, and attenuated apoptosis in CRC cells.

    “In summary, FDFT1 overexpression inhibited cell proliferation and induced G0/G1 phase cell cycle arrest and apoptosis, while FDFT1 knockdown promoted cell proliferation, induced S phase cell cycle arrest, and attenuated apoptosis in CRC cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    When fasting was combined with FDFT1 knockdown in vivo, the inhibitory effect of fasting on CRC was reversed, indicating FDFT1 was an important downstream target of fasting that mediated inhibition of CRC cell proliferation.

    “when fasting was combined with FDFT1 knockdown in vivo, the inhibitory effect of fasting on CRC was reversed, indicating that FDFT1 was an important downstream target of fasting that mediated the inhibition of CRC cell proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FDFT1 expression was negatively correlated with mTOR expression, and mTOR was a potential downstream target of FDFT1 in CRC.

    “our data implied that FDFT1 expression was negatively correlated with mTOR expression, and that mTOR was a potential downstream target of FDFT1 in CRC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FDFT1 negatively regulates proliferation of CRC cells, and acts as a tumor suppressor in CRC.

    “Our study showed that FDFT1 negatively regulates the proliferation of CRC cells, and acts as a tumor suppressor in CRC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Fasting and rapamycin can be potential therapeutic implications to inhibit the proliferation of CRC.

    “these results demonstrated that fasting and rapamycin can be potential therapeutic implications to inhibit the proliferation of CRC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FDFT1 acts at a branch point in the mevalonate pathway, and is the first specific enzyme in cholesterol synthesis, catalyzing the reaction that produces squalene synthase.

    “FDFT1 acts at a branch point in the mevalonate pathway, and is the first specific enzyme in cholesterol synthesis, catalyzing the reaction that produces squalene synthase34,45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Coman, D. et al. Squalene synthase deficiency: clinical, biochemical, and molecular characterization of a defect in cholesterol biosynthesis. Am. J. Hum. Genet. 103, 125–130 (2018). source

      Not checked in the free run.

    • cites [45] Shechter, I. et al. Localization of the squalene synthase gene (FDFT1) to human chromosome 8p22-p23.1. Genomics 20, 116–118 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FDFT1 has seldom been studied in cancer research; limited studies addressed FDFT1 in prostate cancer, ovarian cancer, and lung cancer, but there is no information on the function of FDFT1 in CRC.

    “Limited studies addressed FDFT1 in prostate cancer35, ovarian cancer46, and lung cancer47, but there is no information on the function of FDFT1 in CRC.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [35] Fukuma, Y. et al. Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer. Prostate Cancer Prostatic Dis. 15, 339–345 (2012). source

      Not checked in the free run.

    • cites [46] Zheng, L., Li, L., Lu, Y., Jiang, F. & Yang, X. A. SREBP2 contributes to cisplatin resistance in ovarian cancer cells. Exp. Biol. Med. 243, 655–662 (2018). source

      Not checked in the free run.

    • cites [47] Dehghani, M. et al. Relationship of SNP rs2645429 in farnesyl-diphosphate farnesyltransferase 1 gene promoter with susceptibility to lung cancer. Int J. Genomics 2018, 4863757 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    FDFT1 played an important tumor-suppressive role with clinical significance and function in CRC, and was an important downstream target of fasting.

    “FDFT1 played an important tumor-suppressive role with clinical significance and function in CRC, and was also an important downstream target of fasting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The experiments were repeated at least three times.

    “The experiments were repeated at least three times.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Mice were randomly assigned to the control group or the FMD group when tumors were palpable.

    “When the tumors were palpable, the mice were randomly assigned to the control group or the FMD group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The IHC staining score was determined by two independent pathologists.

    “The staining score was determined by two independent pathologists at our center.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cholesterol deprivation can inhibit tumor growth, decrease phosphorylation of AKT, promote apoptosis, decrease Bcl-xl, downregulate caspase 3 activation, or hinder entry of cells into S phase.

    “cholesterol deprivation can inhibit tumor growth, decrease the phosphorylation of AKT, promote apoptosis62, decrease Bcl-xl, downregulate caspase 3 activation63, or hinder entry of cells into the S phase64.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Zhuang, L., Kim, J., Adam, R. M., Solomon, K. R. & Freeman, M. R. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J. Clin. Investig. 115, 959–968 (2005). source

      Not checked in the free run.

    • cites [63] Li, Y. C., Park, M. J., Ye, S. K., Kim, C. W. & Kim, Y. N. Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am. J. Pathol. 168, 1107–1118 (2006). source

      Not checked in the free run.

    • cites [64] Duncan, R. E., El-Sohemy, A. & Archer, M. C. Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity. J. Biol. Chem. 279, 33079–33084 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    mTOR is a positive regulator of aerobic glycolysis and proliferation in CRC cells.

    “our data showed that mTOR is a positive regulator of aerobic glycolysis and proliferation in CRC cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HIF1α is a key regulator of the Warburg effect and regulates expression of a variety of metabolism-related proteins.

    “HIF1α is a key regulator of the Warburg effect and regulates the expression of a variety of metabolism-related proteins61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Semenza, G. L. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33, 207–214 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Survival data show a worse prognosis of FDFT1-low tumors regardless of expression of other mTOR pathway genes, suggesting an alternative pathway for FDFT1 to effect cancer proliferation potential.

    “The survival data also show a worse prognosis of FDFT1-low tumors regardless of the expression of other mTOR pathway genes, which suggest an alternative pathway for FDFT1 to effect cancer proliferation potential.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways.

    “mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways27,28,40,48.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [27] Mossmann, D., Park, S. & Hall, M. N. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat. Rev. Cancer 18, 744–757 (2018). source

      Not checked in the free run.

    • cites [28] Shih-Chin, C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014). source

      Not checked in the free run.

    • cites [40] Masui, K. et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab. 18, 726–739 (2013). source

      Not checked in the free run.

    • cites [48] Salmond, R. J. mTOR regulation of glycolytic metabolism in T cells. Front. Cell Develop. Biol. 6, 122 (2018). source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    The fasting mimic medium used in vitro and the fasting mimic diet used in mice reproduce the biological effects of fasting.

    “The extracellular acidification rate (ECAR), which is another indicator of glycolysis, was reduced in cells cultured in the fasting mimic medium (Fig. 1h; Supplementary Fig. 2j).”
    “When the tumors were palpable, the mice were randomly assigned to a control or the fasting mimic diet (FMD) group.”

  • The paper relies on this without support.

    Rapamycin is a pharmacological inhibitor of mTOR.

    “rapamycin, a pharmacological inhibitor of mTOR”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Treatments targeting key components of tumor hypoxia signaling pathways, including mTOR, are current approaches to cancer therapy.

    “Treatments targeting key components of tumor hypoxia signaling pathways, including mTOR, are one of the current approaches to cancer therapy.”

    From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [181]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting significance threshold for three stars

    Minor

    The statistical-analysis section defines three stars as P < 0.01, whereas the figure legends define them as P < 0.001.

  • Different genes named for the same Fig. 5 correlation panels

    Minor

    The Fig. 5 caption says panels p-t show a correlation with LDHA, while the Results text says those panels show a correlation with GPI.

  • Conflicting reference numbers for GSE60653

    Minor

    The same fasting-induced anti-Warburg CRC dataset is attributed to reference 28 in the Results and reference 29 in the Discussion.

3 of 3

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Authors
Weng, M.-L., Chen, W.-K., Chen, X.-Y., Lu, H., Sun, Z.-R., Yu, Q., Sun, P.-F., Xu, Y.-J., Zhu, M.-M., Jiang, N., Zhang, J., Zhang, J.-P., Song, Y.-L., Ma, D., Zhang, X.-P., & Miao, C.-H.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Fudan University (CN)
Corresponding author
  • Zhang, Jin
  • Ma, Duan
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-04-20
Volume
11
Issue
1
Pages
1869-1869
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-15795-8
PMC
PMC7170903
OpenAlex
W3017148053
Semantic Scholar
45fe095443b205b87b5a2f43d4bd424cf7e55d3e
Cited by
242
References
70
Citations by year
2026: 8 · 2025: 53 · 2024: 42 · 2023: 54 · 2022: 44 · 2021: 31 · 2020: 7 · 2019: 3
FWCI
20.91
Type
journal article
Language
en
Status
Retracted
Update notices
retraction (2025-10-20)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Shanghai Anti-Cancer Association
  • National Natural Science Foundation of China (81572626, 81372101, 2015ZB0104, SHDC12018105, 81873948, 81871591)
  • National Key Research and Development Program of China (SHDC12018105, 2018YFC2001904, 2015CB553404, 81873948)
Topics
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
fasting, colorectal cancer, FDFT1, aerobic glycolysis, tumor cell proliferation, glucose metabolism, tumor suppressor, mTOR inhibitors
MeSH terms
Animals, Colonic Neoplasms, Disease Models, Animal, Fasting, Female, Glycolysis, Humans, Male, Mice, Inbred BALB C, Middle Aged, Farnesyl-Diphosphate Farnesyltransferase, Colorectal Neoplasms, Signal Transduction, Down-Regulation, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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