**2.2 Importance and effects of phosphorylation of p65 in modulating chemoresistance**

Several studies have indicated a role for NF-κB hyperactivity in the development of resistance to chemotherapeutics via downregulation of antisurvival and upregulation of prosurvival target genes and pathways [42–44]. In one study for example, gemcitabine-resistant pancreatic cancer cells were rendered sensitive to gemcitabine upon knockdown of p65 [42]. These and other accounts of NF-κB-mediated

chemoresistance have been extensively reviewed by others such as Li, Sethi, and Godwin et al., which will not be further discussed in this chapter [45, 46]. However, the specific contribution of dysregulated p65 phosphorylation to chemoresistance is less well understood and requires further exploration. Nonetheless, a few reports suggest that upstream kinases involved in chemoresistance can modulate p65 phosphorylation levels in this context. For instance, siRNA-mediated depletion of IKKα in HT1080 human fibrosarcoma cells was shown to decrease phosphorylation of p65 in response to doxorubicin, thus severely impairing the ability of doxorubicin to initiate NF-κB DNA-binding activity. These findings suggest that IKKα plays a critical role in NF-κB-mediated chemoresistance in response to doxorubicin and potentially serves as a therapeutic target for improving chemotherapeutic response [47]. Other studies have shown that p65, in a hyperphosphorylated state, can be correlated with resistance to thymidylate synthases and irinotecan in stomach and colon cancers, respectively [44, 48, 49]. Doxorubicin resistance in lung cancer has also been correlated with p65 S536 phosphorylation states [47]. Additionally, multiple myelomas have exhibited increased p65 S536 phosphorylation within melphalan- or doxorubicin-resistant cells [50].
