Deep-sea natural compound targets cancer cells through a dual mechanism

A collaborative research team has uncovered a previously unknown mechanism of action of yaku’amide B, a structurally complex peptidic natural product derived from deep-sea sponge found in the waters near Yakushima Island, Japan. Natural products often exhibit multifaceted biological activities due to their structural complexity, interacting transiently with multiple biomolecules. Yaku’amide B was previously shown to inhibit ATP synthase, an essential enzyme for cellular energy production. However, this alone could not fully explain its unique anticancer properties.

To address this, the research team, led by Professor Kaori Sakurai at Tokyo University of Agriculture and Technology, together with Associate Professor Hiroaki Itoh and Professor Masayuki Inoue at Graduate School of Pharmaceutical Sciences, the University of Tokyo, employed photoaffinity labeling (PAL), which allows scientists to “capture” molecules that interact briefly with a drug.

The work was published in the Journal of the American Chemical Society.

Associate Professor Itoh explains that “using a designed PAL probe, we discovered that yaku’amide B transiently binds to CD9, a membrane protein reported as a cancer stem cell marker. Remarkably, we found that this interaction promotes CD9 degradation inside cancer cells. Concurrently, yaku’amide B moves into mitochondria, where it inhibits ATP synthase, leading to cellular energy depletion.”

Professor Sakurai commented on the significance of the findings, saying, “CD9 is considered a key marker of aggressive cancer cells, including those responsible for recurrence and metastasis. Discovering that yaku’amide B can induce CD9 degradation is groundbreaking. This finding opens up new possibilities for drug development strategies that target cancer stem cells and their associated pathways.”

Professor Inoue also notes, “This dual mechanism—ATP depletion and CD9 degradation—provides a compelling explanation for yaku’amide B’s ability to suppress both cancer cell proliferation and migration.

“Yaku’amide B is the first natural product reported to induce CD9 degradation, highlighting PAL as a powerful strategy for studying transient interactions and paving the way for next-generation anticancer drugs that simultaneously target multiple cellular functions.”

The study underscores the potential of natural products as starting points for innovative therapeutic approaches, including multi-target drug design and protein degradation strategies, offering new hope for future cancer treatments.