CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling.
Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-kappaB-dependent manner. Moreover, CNK1 cooperates with the NF-kappaB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-kappaB pathway because knockdown of CNK1 interferes with processing of NF-kappaB2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1-depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy.
Fritz
Rafael D
RD
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Radziwill
Gerald
G
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism
C500833:CNKSR1 protein, human; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C497593:RELB protein, human; D034741:RNA, Small Interfering; D051841:Transcription Factor RelB; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1