Long associated with decreased risk of cancer, broccoli and other cruciferous vegetables—the family of plants that also includes cauliflower, cabbage, collard greens, Brussels sprouts and kale—have now been found to contain a molecule that inactivates a gene known to play a role in a variety of common human cancers.
In a new paper published May 16 in Science, researchers led by Pier Paolo Pandolfi, the HMS Victor J. Aresty Professor of Medicine at Beth Israel Deaconess Medical Center, demonstrate that targeting the gene, known as WWP1, with the ingredient found in broccoli suppressed tumor growth in cancer-prone lab animals.
“We found a new important player that drives a pathway critical to the development of cancer, an enzyme that can be inhibited with a natural compound found in broccoli and other cruciferous vegetables,” said Pandolfi, who is also director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess.
“This pathway emerges not only as a regulator for tumor growth control, but also as an Achilles’ heel we can target with therapeutic options,” Pandolfi said.
One of the most frequently mutated, deleted, downregulated or silenced tumor suppressor genes in human cancersis PTEN. Certain inherited PTEN mutations can cause syndromes characterized by cancer susceptibility and developmental defects.
Because complete loss of the gene triggers an irreversible and potent failsafe mechanism that halts proliferation of cancer cells, it’s rare for both copies of the gene (humans have one copy from each parent) to be affected. Instead, tumor cells exhibit lower levels of PTEN. This raises the question of whether restoring PTEN activity to normal levels in the cancer setting can unleash the gene’s tumor-suppressive activity.
To find out, Pandolfi and colleagues identified the molecules and compounds regulating PTEN function and activation.
Carrying out a series of experiments in cancer-prone mice and human cells, the team revealed that a gene called WWP1, which is also known to play a role in the development of cancer, produces an enzyme that inhibits PTEN’s tumor-suppressive activity.
How to disable this PTEN kryptonite?
By analyzing the enzyme’s physical shape, the research team’s chemists recognized that a small molecule—formally named indole-3-carbinol (I3C), an ingredient in broccoli and its relatives—could be the key to quelling the cancer-causing effects of WWP1.
When Pandolfi and colleagues tested this idea by administering I3C to cancer-prone lab animals, they found that it inactivated WWP1, releasing the brakes on PTEN’s tumor-suppressive power.
But don’t head to the farmer’s market just yet. First author Yu-Ru Lee, HMS research fellow in medicine and a member of the Pandolfi lab, notes you’d have to eat nearly six pounds of Brussels sprouts a day, and uncooked ones at that, to reap their potential anti-cancer benefit.
That’s why the Pandolfi team is seeking other ways to leverage this new knowledge. The team plans to further study the function of WWP1 with the ultimate goal of developing more potent, and practical, WWP1 inhibitors.
Genetic or pharmacological inactivation of WWP1 with either CRISPR technology or I3C could “restore PTEN function and further unleash its tumor suppressive activity,” said Pandolfi. “These findings pave the way toward a long-sought tumor suppressor reactivation approach to cancer treatment.”
This work was mainly supported by the National Institutes of Health (grants R01CA82328 and R35CA197529).
In addition to Pandolfi and Lee, authors include Ming Chen, Jonathan D. Lee, Jinfang Zhang, Tomoki Ishikawa, Jesse M. Katon, Yang Zhang, Yulia V. Shulga, Assaf C. Bester, Jacqueline Fung, Emanuele Monteleone, Lixin Wan, John G. Clohessy, and Wenyi Wei, all of Beth Israel Deaconess; Shu-Yu Lin, Shang-Yin Chiang and Ruey-Hwa Chen of the Institute of Biological Chemistry; Tian-Min Fu and Chen Shen of Harvard Medical School; Chih-Hung Hsu, Hao Chen and Hao Wu of Boston Children’s Hospital; Antonella Papa of Monash University; Julie Teruya-Feldstein of Icahn School of Medicine at Mount Sinai; Suresh Jain of Intonation Research Laboratories; and Lydia Matesic of the University of South Carolina.
Disclosures: Pandolfi, Wei and Jain are cofounders of Rekindle Pharmaceuticals, which is developing novel therapies for cancer. All other authors declare no competing interests.
Adapted from a Beth Israel Deaconess news release.