Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB

Abstract

The abilities of NF-κB to promote cell proliferation, suppress apoptosis, promote cell migration, and suppress differentiation apparently have been co-opted by cellular and viral oncoproteins to promote oncogenesis (Figure 2). Direct evidence, using both in vitro and in vivo models, indicates that NF-κB is required for oncogenesis, probably at multiple levels. NF-κB likely plays an important role in the early events of oncogenesis, possibly functioning primarily in protecting against transformation-associated apoptosis. In most late-stage tumor cells, classic NF-κB (the p50-p65 heterodimer) is clearly not the only survival factor, because its inhibition does not induce apoptosis in many of these tumor cells. This observation suggests that other events have occurred to upregulate NF-κB-independent cell survival pathways. However, clearly some cancer cells depend on NF-κB for their survival. NF-κB also can contribute to cell progression by transcriptionally upregulating cyclin D1 with corresponding hyperphosphorylation of the tumor suppressor protein Rb. The induction of NF-κB-controlled proliferation may correlate with loss of differentiation in certain settings (47), which may promote oncogenesis. NF-κB is known to regulate certain genes associated with metastasis, such as matrix metalloproteinase 9, tissue plasminogen activator, and ICAM-1. Thus, a more relevant role for NF-κB in later-stage oncogenesis may be to promote metastasis and angiogenesis. Although many tumor cells display some level of constitutive nuclear NF-κB, higher levels of NF-κB and the transcriptional potential of NF-κB can be further enhanced in response to certain types of chemotherapy. Consistent with this, inhibition of NF-κB in parallel with certain (but apparently not all) chemotherapy treatments strongly enhances the apoptotic potential of the chemotherapy. This observation indicates that NF-κB plays an important role in inducible chemoresistance and establishes NF-κB inhibition as a new adjuvant approach in chemotherapy.