Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion.
Obesity is a significant risk factor for post-menopausal women to develop             and die from breast cancer. Leptin, an adipokine is produced in high levels in             obese individuals, and its receptor is overexpressed in breast tumors and lymph             node metastases. Previously, we demonstrated that leptin stimulates breast cancer             cell invasion, which is correlated with breast cancer metastasis. Programmed cell             death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether             PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we             report the novel findings that leptin failed to induce invasion in MCF-7 breast             cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2             (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated             the invasion of MCF-7/PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2             knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated             kinases 1,2 and signal transducer and activator of transcription 3, but not that             of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert             its anti-invasive effect by suppressing leptin-induced activation of extracellular             signal-regulated kinases 1,2 and signal transducer and activator of transcription             3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast             tumors may be able to stop obesity-related breast tumor progression and prolong             the life of patients.
Departamento de Bioquímica, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, N.L., Mexico.
Vianey
V
González-Villasana
René
R
Nieves-Alicea
Vanity
V
McMurtry
Yolanda
Y
Gutiérrez-Puente
Ana M
AM
Tari
D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D020738:Leptin; C114487:PDCD4 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D048031:JNK Mitogen-Activated Protein Kinases