Programmed cell death 4 inhibits breast cancer cell invasion by increasing tissue inhibitor of metalloproteinases-2 expression.
High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E(2) (PGE(2)) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE(2) and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE(2) and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE(2) and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE(2) and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE(2) and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE(2) and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.
Nieves-Alicea
René
R
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 422, Houston, TX 77030, USA.
Colburn
Nancy H
NH
Simeone
Ann-Marie
AM
Tari
Ana M
AM
D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D016209:Interleukin-8; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone