Researchers report in Science that indole-3-carbinol (I3C) – a natural compound found in broccoli – can be used to therapeutically target a gene (WWP1) known to play a role in several human cancers. Using mouse and human cell models, the team were able to demonstrate that I3C is in fact a potent inhibitor of the enzyme WWP1 (WW domain–containing ubiquitin E3 ligase 1).
"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," explains corresponding author of the study Pier Paolo Pandolfi, MD, PhD in a recent press release.
"This pathway emerges not only as a regulator for tumor growth control, but also as an Achilles' heel we can target with therapeutic options."
Combating cancer with indole-3-carbinol
I3C is a breakdown product of glucosinolate glucobrassicin which can be found in broccoli, cauliflower, cabbage, collard greens, and Brussel sprouts.
Using molecular modeling, Pandolfi and colleagues determined that I3C could successfully bind to a specific domain very similar to the HECT catalytic domain of WWP1, therefore they sought to investigate whether I3C might inhibit WWP1.
WWP1 is often overexpressed and genetically amplified in numerous types of cancer such as prostate and breast. It is also able to associate with and inhibit PTEN – a critical tumor suppressive phosphatase.
The PTEN gene is commonly mutated, deleted, down-regulated or silenced in human cancers, where tumor cells exhibit reduced levels of “active” PTEN. By inhibiting WWP1 (via pharmacological inhibition [I3C] or genetic ablation) the researchers found it was possible to “reactivate” PTEN, restoring its activity and tumor suppressive power – reducing the growth and survival of the tumor cells.
"Either 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."
The team intends to further study the function of WWP1 with the hopes of developing more potent WWP1 inhibitors in the future.
Reference: Yu-Ru Lee, et al. (2019) Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway, Science 364, eaau0159