Conditional ablation of Ikkb inhibits melanoma tumor development in mice

Abstract

Several lines of evidence suggest that tumor cells show elevated activity of the NF-κB transcription factor, a phenomenon often resulting from constitutive activity of IκB kinase β (IKKβ). However, others have found that loss of NF-κB activity or IKKβ is tumor promoting. The role of NF-κB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKβ in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRas V12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf -/-mice with melanocyte-specific deletion of Ikkb were protected from HRas V12 -initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkβ-mediated NF-κB activity.

IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia

“…Although the response to altered NFkB activity varies among different cell types, increased NFkB activity is usually associated with tumor development (1,32). IKKb also acts as a tumor promoter in different cell types, as it happens in colitis-associated cancer and melanoma development in animal models, as well as in human breast cancer patients (33)(34)(35). In the case of oral epithelia, we have observed inflammation and basal cell damage as a consequence of targeted overexpression of IKKb.…”

Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice

“…This releases the p65/p50 NF-κB heterodimer, allowing its nuclear translocation and promoter binding for inflammatory gene transcription. A series of studies has indicated a requirement of Ikk2 and p65 in both murine and human Kras-induced transformation of lung epithelial cells and in models of inflammation-induced carcinogenesis (7,8,10,11). However, the implication of the pathway in pancreatic cancer has so far been unexplored.…”

Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice

“…Many cancer cell lines, but also primary tumors, display constitutively increased NF-κB activity, and inhibition of NF-κB compromises the survival and growth of cultured cancer cells, suggesting that NF-κB is important for the survival of at least some types of tumors (1). Furthermore, NF-κB inhibition diminished tumor development in mouse models, supporting an important role for NF-κB in carcinogenesis (2)(3)(4)(5)(6).…”

“…However, NF-κB inhibition in skin or liver cells had opposite effects in different models of carcinogenesis. NF-κB inhibition by expression of IκBα-SR in epidermal keratinocytes synergized with oncogenic Ras to induce epidermal cancer (11) or led to spontaneous tumor development (12), while IKK2 ablation in melanocytes protected mice from oncogenic Ras-induced melanoma development (2). Moreover, NF-κB blockade by IκBα-SR expression in hepatocytes inhibited inflammation-associated liver cancer development in the Mdr2-deficient mouse model (3), while IKK2 ablation in hepatocytes sensitized mice to chemical hepatocarcinogenesis induced by diethylnitrosamine (DEN) (13).…”