Research article summary (published 13 Aug 2008):

Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2.

Full 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.

Author information

Author/s: Fehrenbacher, Nicole (N); Bastholm, Lone (L); Kirkegaard-Sørensen, Thomas (T); Rafn, Bo (B); Bøttzauw, Trine (T); Nielsen, Christina (C); Weber, Ekkehard (E); Shirasawa, Senji (S); Kallunki, Tuula (T); Jäättelä, Marja (M);

Affiliation: Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Cancer research (Cancer Res), published in United States. (Language: eng)

Reference: 2008-Aug; vol 68 (issue 16) : pp 6623-33

Dates: Created 2008/08/14; Completed 2008/10/02;

PMID: 18701486, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects; physiology Cathepsins - metabolism Cell Communication Cell Membrane Permeability Cell Transformation, Neoplastic Cells, Cultured Colonic Neoplasms - metabolism; pathology Down-Regulation Embryo, Mammalian - cytology; drug effects; metabolism Extracellular Signal-Regulated MAP Kinases - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism Fibroblasts - cytology; drug effects; metabolism Genes, ras - physiology Humans Lysosomal-Associated Membrane Protein 1 - genetics; metabolism Lysosomal-Associated Membrane Protein 2 - genetics; metabolism Lysosomes - drug effects; metabolism Mice NIH 3T3 Cells Proto-Oncogene Proteins c-raf - metabolism Proto-Oncogene Proteins p21(ras) - physiology RNA Interference

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Antineoplastic Agents (0) ; Lysosomal-Associated Membrane Protein 1 (0) ; Lysosomal-Associated Membrane Protein 2 (0) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.1.37) ; Proto-Oncogene Proteins c-raf (EC 2.7.1.37) ; Cathepsins (EC 3.4.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)

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