Abstract
Expression and activity of lysosomal cysteine cathepsins correlate with the metastatic capacity and aggressiveness of tumors. Here, we show that transformation of murine embryonic fibroblasts with v-H-ras or c-src(Y527F) changes the distribution, density, and ultrastructure of the lysosomes, decreases the levels of lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in an extracellular signal-regulated kinase (ERK)- and cathepsin-dependent manner, and sensitizes the cells to lysosomal cell death pathways induced by various anticancer drugs (i.e., cisplatin, etoposide, doxorubicin, and siramesine). Importantly, K-ras and erbb2 elicit a similar ERK-mediated activation of cysteine cathepsins, cathepsin-dependent down-regulation of LAMPs, and increased drug sensitivity in human colon and breast carcinoma cells, respectively. Notably, reconstitution of LAMP levels by ectopic expression or by cathepsin inhibitors protects transformed cells against the lysosomal cell death pathway. Furthermore, knockdown of either lamp1 or lamp2 is sufficient to sensitize the cells to siramesine-induced cell death and photo-oxidation-induced lysosomal destabilization. Thus, the transformation-associated ERK-mediated up-regulation of cysteine cathepsin expression and activity leads to a decrease in the levels of LAMPs, which in turn contributes to the enhanced sensitivity of transformed cells to drugs that trigger lysosomal membrane permeabilization. These data indicate that aggressive cancers with high cysteine cathepsin levels are especially sensitive to lysosomal cell death pathways and encourage the further development of lysosome-targeting compounds for cancer therapy.
Highlights
IntroductionLysosomes are highly dynamic cytosolic organelles that receive membrane traffic input from the biosynthetic (trans-Golgi network), endocytic, and autophagic pathways [1, 2]
Lysosomes are highly dynamic cytosolic organelles that receive membrane traffic input from the biosynthetic, endocytic, and autophagic pathways [1, 2]
Immortalization of murine embryonic fibroblasts as well as their subsequent transformation by viral Harvey ras (v-H-ras) and c-srcY527F oncogenes sensitize them to cathepsin-mediated cell death induced by tumor necrosis factor (TNF) and siramesine [17, 24]
Summary
Lysosomes are highly dynamic cytosolic organelles that receive membrane traffic input from the biosynthetic (trans-Golgi network), endocytic, and autophagic pathways [1, 2]. They contain more than 50 hydrolases that can process all the major macro-. Cathepsin proteases are among the beststudied lysosomal hydrolases. They are maximally active at the acidic pH of lysosomes (pH 4–5). Once outside the tumor cells, cathepsins stimulate angiogenesis, tumor growth, and invasion in murine cancer models, thereby enhancing cancer progression [7, 8]. The maintenance of lysosomal membrane integrity is of utmost importance for the cell survival
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