An Ursolic Acid Derived Small Molecule Triggers Cancer Cell Death through Hyperstimulation of Macropinocytosis

Macropinocytosis
is a transient endocytosis that internalizes extracellular
fluid and particles into vacuoles. Recent studies suggest that hyperstimulation
of macropinocytosis can induce a novel nonapoptotic cell death, methuosis.
In this report, we describe the identification of an ursolic acid
derived small molecule (compound 17), which induces cancer
cell death through hyperstimulation of macropinocytosis. 17 causes the accumulation of vacuoles derived from macropinosomes
based on transmission electron microscopy, time-lapse microscopy,
and labeling with extracellular fluid phase tracers. The vacuoles
induced by 17 separate from other cytoplasmic compartments
but acquire some characteristics of late endosomes and lysosomes.
Inhibiting hyperstimulation of macropinocytosis with the specific
inhibitor amiloride blocks cell death, implicating that 17 leads to cell death via macropinocytosis, which is coincident with
methuosis. Our results uncovered a novel cell death pathway involved
in the activity of 17, which may provide a basis for
further development of natural-product-derived scaffolds for drugs
that trigger cancer cell death by methuosis.