Depletion of procathepsin D gene expression by RNA interference: a potential therapeutic target for breast cancer.

Abstract

Elevated level of procathepsin D (pCD), a zymogen of lysosomal aspartic proteinase cathepsin D, is associated with highly invasive neoplasms that include breast cancer. Independent studies have established that secreted pCD functions as a growth factor acting both in an autocrine and paracrine manner. Therefore, to explore whether pCD can be employed as a therapeutic target, the present study evaluates the impact of pCD knockdown using RNA interference technology. Of the three siRNA oligos tested, siRNA-3 exhibited a 90% inhibitory effect on pCD gene expression. Stable attenuation of pCD in breast cancer cells MDA-MB-231 was achieved by using a plasmid vector-based shRNA system. Pronounced suppression of pCD expression was accompanied by a significant reduction in invasion and proliferation of MDA-MB-231 cells stably transfected with functional shRNA. Importantly, in the athymic nude mice model, downregulation of pCD in breast cancer cells significantly reduced their metastatic potential. In addition, we observed a reduction in Cdc42 and NFkappaB2 expression in MDA-MB-231 cells with decreased pCD expression. When combined, our in vitro and in vivo experiments demonstrate that targeting pCD through RNAi technology represents a potential therapeutic tool for developing a therapy against breast cancer.

• Authors: Sujata Saraswat Ohri, Aruna Vashishta, Mary Proctor, Martin Fusek, Vaclav Vetvicka
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 7 Pg. 1081-7 (Jul 2007) ISSN: 1538-4047 [Print] United States
• PMID: 17611405 (Publication Type: Journal Article)

Chemical References

• Enzyme Precursors
• NF-kappa B p50 Subunit
• NFKB1 protein, human
• RNA, Small Interfering
• procathepsin D
• Cathepsin D
• cdc42 GTP-Binding Protein

Topics

• Animals
• Breast Neoplasms (pathology, therapy)
• Cathepsin D (antagonists & inhibitors, genetics)
• Cell Line, Tumor
• Cell Proliferation
• Enzyme Precursors (antagonists & inhibitors, genetics)
• Female
• Humans
• Mice
• NF-kappa B p50 Subunit (antagonists & inhibitors)
• Neoplasm Invasiveness
• RNA Interference
• RNA, Small Interfering (genetics)
• cdc42 GTP-Binding Protein (antagonists & inhibitors)