July 14, 2024

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Iron in Red Meat May Promote Colon Cancer!

Iron in Red Meat May Promote Colon Cancer!



Iron in Red Meat May Promote Colon Cancer! Scientists Discover Iron Ions in Red Meat Activate Telomerase and Promote Colon Cancer Progression.

Consuming large amounts of red meat has long been associated with an increased risk of colon cancer, a link repeatedly confirmed by various epidemiological studies. Numerous carcinogenic substances and mechanisms within red meat have been identified. However, driven by the desire to eradicate all contributing factors, the scientific community continues to search for additional culprits. Today, a surprising suspect has been identified—iron.

Researchers from the Agency for Science, Technology and Research (A*STAR) in Singapore and the National Cancer Centre Singapore have published their findings in the journal Cancer Discovery. They discovered that iron ions (Fe3+) found in red meat are utilized by a protein called Pirin to reactivate the catalytic subunit of telomerase (hTERT). This reactivation promotes the progression of colon cancer by enabling cancer cells to achieve “immortality.” Fortunately, the researchers have also identified an hTERT inhibitor.

Iron in Red Meat May Promote Colon Cancer! Scientists Discover Iron Ions in Red Meat Activate Telomerase and Promote Colon Cancer Progression.

Previous studies have shown that hTERT is the rate-limiting subunit of telomerase, with its activity directly determining telomerase’s overall activity. Elevated telomerase activity helps cancer cells maintain their telomere length, allowing them to proliferate continuously. High expression of hTERT has been detected in many solid tumors and is often associated with poor patient prognosis. The Singapore researchers aimed to find a drug that could regulate hTERT and, consequently, telomerase activity.

Using NanoLuc technology and high-throughput screening, the researchers identified a small molecule drug called SP2509. This drug effectively reduces hTERT mRNA levels and telomerase activity, despite its original function of inhibiting the histone demethylase LSD1. The study revealed that SP2509 binds to Pirin protein, enhancing its stability, rather than affecting LSD1 expression.

Now, how does this research relate to red meat, iron, and colon cancer? Previous studies have shown that the activity of Pirin protein is significantly influenced by its binding with iron ions. Given that SP2509 binds to Pirin and regulates hTERT expression, it suggests that iron ions also play a role in regulating telomerase activity through hTERT. To test this hypothesis, colon cancer was used as the research model.

Analysis of 40 recently removed colon cancer samples showed that 12 samples had significantly increased telomerase activity, with 10 of these also having high concentrations of iron ions. This high correlation (only one sample with high iron ions did not show increased telomerase activity) strongly indicates a close relationship between the two. Single-cell sequencing further confirmed that cell subgroups with high hTERT expression (indicating high telomerase activity) also had high expression of genes related to Pirin protein and iron ion metabolism.

The researchers then proceeded to unravel the mechanism by which Pirin protein and iron ions regulate hTERT and telomerase activity. Pirin has transcriptional regulatory functions that depend on its binding with iron ions. The small molecule inhibitor SP2509 competitively binds with Pirin, weakening its regulatory effect on hTERT.

In other words, Pirin’s regulation of hTERT is iron ion-dependent, which explains the positive correlation between Pirin protein levels, iron ion levels, and hTERT activity in colon cancer. Further analysis revealed that after binding with iron ions, Pirin competes with the transcription factor NFAT-1, negatively regulating the E3 ubiquitin ligase FBXW7. This enhances the stability of the important transcription factor Sp1, which then positively regulates the hTERT gene promoter.

Enhanced hTERT activity under Pirin regulation has negative implications for cancer treatment. Therefore, SP2509’s ability to inhibit Pirin confers anti-cancer effects, as demonstrated in subsequent cell experiments. Notably, metabolic subtype colon cancer cells (CMS3 type, characterized by KRAS mutations) showed the most significant inhibition. However, SP2509 was ineffective against cancer cells with hTERT gene mutations, which occur in approximately 20% of cases.

Epidemiological studies have previously been inconclusive regarding the link between dietary iron and colon cancer, and interventions were not considered. This study, however, suggests that iron ions in red meat do play a role in promoting colon cancer. From a therapeutic perspective, using iron ions as biomarkers to target hTERT for precision treatment appears feasible, as normal cells generally do not express hTERT, making it an ideal therapeutic target.

Iron in Red Meat May Promote Colon Cancer!


References:

[1]Shanmugam R, Majee P, Shi W, et al. Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers[J]. Cancer Discovery, 2024.

[2]Wang K, Wang R L, Liu J J, et al. The prognostic significance of hTERT overexpression in cancers: A systematic review and meta-analysis[J]. Medicine, 2018, 97(35): e11794.

[3]Leão R, Apolónio J D, Lee D, et al. Mechanisms of human telomerase reverse transcriptase (h TERT) regulation: clinical impacts in cancer[J]. Journal of Biomedical Science, 2018, 25: 22.

[4]Valenzuela G, Canepa J, Simonetti C, et al. Consensus molecular subtypes of colorectal cancer in clinical practice: a translational approach[J]. World Journal of Clinical Oncology, 2021, 12(11): 1000.

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