Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Xue, Xiang; Ramakrishnan, S; Weisz, K; Triner, Daniel; Xie, Liwei; Attili, Durga; Pant, Asha; Győrffy, Balázs; Zhan, Mingkun; Carter‐Su, Christin; Hardiman, Karin M.; Wang, Thomas D.; Dame, Michael K.; Varani, James; Brenner, Dean E.; Fearon, Eric R.; Shah, Yatrik M.

doi:10.1016/j.cmet.2016.07.015

Cited by 202 publications

(185 citation statements)

References 51 publications

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“…The AOM-DSS study was done as previously described (26). At the end of the experiment, high-resolution mouse endoscopy was performed to identify colon adenomas as previously described (26). Next, 1 mg/mL DFP and 0.064% Tempol were given in the drinking water.…”

Section: Methodsmentioning

confidence: 99%

“…F/+ mice were described previously (26,40). For chemical-induced (Magnification: B, 40×; E, Upper, 5×, Lower, 8×.)…”

Section: Methodsmentioning

confidence: 99%

“…Humanized gnotobiotic mice were treated with or without 1 mg/mL DFP in the drinking water in last 2 wk. The AOM-DSS study was done as previously described (26). At the end of the experiment, high-resolution mouse endoscopy was performed to identify colon adenomas as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative Real-Time RT-PCR. RNA isolation and qPCR was performed as previously described (26). Primers are listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…To further understand if HIF-2α is involved in the regulation of STEAP4 in CRC, a colon-specific disruption of HIF-2α in the colon-specific sporadic CRC model was assessed (26). Interestingly, disruption of HIF-2α significantly reduced tumoral STEAP4 expression (Fig.…”

Section: Steap4 Is Critical For Colon Tumorigenesis Following Inflammmentioning

confidence: 99%

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Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Xue

Bredell

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and is a major risk factor for colorectal cancer (CRC). Hypoxia is a feature of IBD and modulates cellular and mitochondrial metabolism. However, the role of hypoxic metabolism in IBD is unclear. Because mitochondrial dysfunction is an early hallmark of hypoxia and inflammation, an unbiased proteomics approach was used to assess the mitochondria in a mouse model of colitis. Through this analysis, we identified a ferrireductase: six-transmembrane epithelial antigen of prostate 4 (STEAP4) was highly induced in mouse models of colitis and in IBD patients. STEAP4 was regulated in a hypoxia-dependent manner that led to a dysregulation in mitochondrial iron balance, enhanced reactive oxygen species production, and increased susceptibility to mouse models of colitis. Mitochondrial iron chelation therapy improved colitis and demonstrated an essential role of mitochondrial iron dysregulation in the pathogenesis of IBD. To address if mitochondrial iron dysregulation is a key mechanism by which inflammation impacts colon tumorigenesis, STEAP4 expression, function, and mitochondrial iron chelation were assessed in a colitis-associated colon cancer model (CAC). STEAP4 was increased in human CRC and predicted poor prognosis. STEAP4 and mitochondrial iron increased tumor number and burden in a CAC model. These studies demonstrate the importance of mitochondrial iron homeostasis in IBD and CRC.

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Section: Methodsmentioning

confidence: 99%

“…F/+ mice were described previously (26,40). For chemical-induced (Magnification: B, 40×; E, Upper, 5×, Lower, 8×.)…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Quantitative Real-Time RT-PCR. RNA isolation and qPCR was performed as previously described (26). Primers are listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Section: Steap4 Is Critical For Colon Tumorigenesis Following Inflammmentioning

confidence: 99%

See 3 more Smart Citations

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Xue

Bredell

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Transferrin Receptor‐Mediated Iron Uptake Promotes Colon Tumorigenesis

et al. 2023

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Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss-driven 𝜷-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates 𝜷-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the 𝜷-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.

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Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS‐mediated pathways

Chuang,

Chan,

Shih

2024

BioFactors

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The rising incidence of colorectal cancer (CRC) poses significant healthcare challenges. This study explored the therapeutic potential of combined curcumin (CUR) and metformin (MET) treatment in CRC models. Our findings indicate that the combination treatment (COMB) effectively downregulates the expression of divalent metal transporter‐1 (DMT‐1), leading to a reduction in cell proliferation aligned with suppression of the pAKT/mTOR/Cyclin D1 signaling pathway. The COMB increased reactive oxygen species (ROS) production, triggering activation of the NRF2/KEAP1 pathway. This pathway elicits an antioxidant response to manage oxidative stress in CRC cell lines. Interestingly, the response of NRF2 varied between CT26 and HCT116 cells. Moreover, our study highlights the induction of apoptosis and autophagy, as evidenced by upregulations in Bax/Bcl‐2 ratios and autophagy‐related protein expressions. Notably, the COMB promoted lipid peroxidation and downregulated xCT levels, suggesting the induction of ferroptosis. Ferroptosis has been shown to activate autophagy, which helps eliminate cells potentially damaged by the increased oxidative stress. Furthermore, the COMB effectively diminished the migratory ability of CRC cells. In vivo experiments using CRC‐bearing mouse models, the results confirmed the anti‐tumor efficacy of the COMB, leading to substantial inhibition of tumor growth without inducing general toxicity. In conclusion, our study suggests that combining CUR with MET holds promise as a potential option for CRC treatment, with critical mechanisms likely involving ROS elevation, autophagy, and ferroptosis.

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Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Cited by 202 publications

References 51 publications

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Transferrin Receptor‐Mediated Iron Uptake Promotes Colon Tumorigenesis

Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS‐mediated pathways

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