Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells.

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms.

Galactosyl- and glucosylsphingosine induce lysosomal membrane permeabilization and cell death in cancer cells.

Isomeric lysosphingolipids, galactosylsphingosine (GalSph) and glucosylsphingosine (GlcSph), are present in only minute levels in healthy cells. Due to defects in their lysosomal hydrolysis, they accumulate at high levels and cause cytotoxicity in patients with Krabbe and Gaucher diseases, respectively. Here, we show that GalSph and GlcSph induce lysosomal membrane permeabilization, a hallmark of lysosome-dependent cell death, in human breast cancer cells (MCF7) and primary fibroblasts.

Control of mitosis, inflammation, and cell motility by limited leakage of lysosomes.

Lysosomal membrane permeabilization and subsequent leakage of lysosomal hydrolases into the cytosol are considered as the major hallmarks of evolutionarily conserved lysosome-dependent cell death. Contradicting this postulate, new sensitive methods that can detect a minimal lysosomal membrane damage have demonstrated that lysosomal leakage does not necessarily equal cell death. Notably, cells are not only able to survive minor lysosomal membrane permeabilization, but some of their normal functions actually depend on leaked lysosomal hydrolases.