by Agency for Science, Technology and Research (A*STAR), Singapore

Identification of SP2509 and its target Pirin as a regulator of hTERT in colorectal cancer. Credit: Cancer Discovery (2024). https://doi.org/10.1158/2159-8290.CD-23-1379

Scientists at the Agency for Science, Technology and Research (A*STAR) along with collaborators from the National Cancer Centre Singapore (NCCS) have uncovered a critical link between the overconsumption of red meat and an increased risk of colorectal cancer. Their findings pave the way for new therapeutic approaches targeting telomerase, an enzyme implicated in cancer progression.

Colorectal cancer, which affects the colon or rectum, is the third most common cancer globally and the second leading cause of cancer-related deaths in Singapore. While it is known that both genetics and lifestyle factors, such as diet, contribute to its development, the exact mechanism linking excessive red meat consumption to cancer has remained unclear—until now.

In a study published in the journal Cancer Discovery, the researchers discovered that iron from red meat reactivates telomerase, an enzyme that extends the ends of DNA chromosomes, driving the progression of colorectal cancer. This breakthrough offers crucial insights into how dietary habits influence cancer development.

Promising new therapeutic approach

The study also identified a promising new treatment approach. The research team found that a small molecule, SP2509, can block the reactivation of telomerase in cancer cells by inhibiting iron's interaction with the enzyme. In laboratory tests using cancer cell lines, SP2509 not only halted telomerase reactivation but also reduced tumor growth, presenting a new strategy for combating colorectal cancer.

Scientists from A*STAR Institute for Molecular and Cell Biology (IMCB) led the cross-disciplinary team that included scientists from A*STAR Genome Institute of Singapore (GIS), as well as clinicians from Singapore General Hospital (SGH) and NCCS.

"Understanding the role of iron in telomerase activation opens up new avenues for addressing colorectal cancer," said Professor Vinay Tergaonkar, Distinguished Principal Investigator at A*STAR IMCB.

"Our future research will focus on refining therapeutic strategies that target this mechanism, with the hope of developing more effective treatments for patients, particularly those with high iron levels. We are excited about the potential of small molecules like SP2509 to revolutionize cancer care and improve outcomes for patients globally."

Research insights and methodology

To uncover how high iron levels contribute to colorectal cancer progression, the team studied samples from colorectal cancer patients, using a combination of human colorectal cancer cell lines and advanced laboratory models. By collaborating with clinicians from NCCS, they demonstrated that iron interacts with an iron-sensing protein called Pirin, leading to the reactivation of telomerase in cancer cells—a key factor in their unchecked growth.

Further chemical screens on human colorectal cell lines identified the small molecule SP2509, which competes with iron for binding to Pirin, effectively inhibiting telomerase reactivation. These findings not only offer a novel treatment approach but also provide valuable insight into the molecular pathways linking high intake of iron-rich red meats to colorectal cancer.

Colo-SCRIPT, the national research program that aims to harness insights on distinct colorectal cancer subtypes to reduce cancer incidence and enhance patient outcomes, will leverage these findings under the program's theme to establish the role of environmental, metabolic and microbial risk factors enabling disease progression.

"Through Colo-SCRIPT, we will continue to investigate the role of iron and other risk factors and their influence on how colorectal cancer develops. Findings provide valuable insights into how they drive different subtypes of colorectal cancer and can allow us to identify novel methods to prevent and treat the disease," said Associate Professor Iain Tan, Senior Consultant in the Division of Medical Oncology, NCCS.

More information: Raghuvaran Shanmugam et al, Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers, Cancer Discovery (2024). DOI: 10.1158/2159-8290.CD-23-1379

Journal information: Cancer Discovery 

Provided by Agency for Science, Technology and Research (A*STAR), Singapore