Induction of senescence in melanoma: thinking outside the cell

Pigment Cell & Melanoma Research (Impact Factor: 4.62). 10/2011; 24(5):874-5. DOI: 10.1111/j.1755-148X.2011.00895.x
Source: PubMed
2 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abundant evidence points to a crucial physiological role for cellular senescence in combating tumorigenesis. Thus, the engagement of senescence may represent a key component for therapeutic intervention in the eradication of cancer. In this Opinion article, we focus on concepts that are relevant to a pro-senescence approach to therapy and we propose potential therapeutic strategies that aim to enhance the pro-senescence response in tumours.
    Nature Reviews Cancer 06/2011; 11(7):503-11. DOI:10.1038/nrc3057 · 37.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that NF-kappaB is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IkappaBalphaM-mediated inhibition of constitutive NF-kappaB activity in human pancreatic cancer cells suppressed tumorigenesis and liver metastasis in an orthotopic nude mouse model, suggesting that constitutive NF-kappaB activation plays an important role in pancreatic tumor progression and metastasis. However, the underlying mechanism by which NF-kappaB is activated in pancreatic cancer remains to be elucidated. In this study, we found that an autocrine mechanism accounts for the constitutive activation of NF-kappaB in metastatic human pancreatic cancer cell lines. Further investigation showed that interleukin-1alpha was the primary cytokine secreted by these cells that activates NF-kappaB. Neutralization of interleukin-1alpha activity suppressed the constitutive activation of NF-kappaB and the expression of its downstream target gene, urokinase-type plasminogen activator, in metastatic pancreatic cancer cell lines. Our results demonstrate that regulation of interleukin-1alpha expression is primarily dependent on AP-1 activity, which is in part induced by signaling pathways that are epidermal growth factor receptor-dependent and -independent. In conclusion, our findings suggest a possible mechanism for the constitutive activation of NF-kappaB in metastatic human pancreatic cancer cells and a possible missing mechanistic link between inflammation and cancer.
    Journal of Biological Chemistry 05/2004; 279(16):16452-62. DOI:10.1074/jbc.M309789200 · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.
    Cell 03/2008; 132(3):363-74. DOI:10.1016/j.cell.2007.12.032 · 32.24 Impact Factor