Wip1 is a stress-response
phosphatase that negatively regulates several
tumor suppressors, including p53. In a sizeable fraction of
tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these
tumors. However, over half of human
tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in
cancer cells lacking wild type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer
drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the
pro-apoptotic protein Bax and decreased levels of the
anti-apoptotic protein Bcl-xL. We showed that interaction of Wip1 and the
transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased
drug sensitivity only in the p53-negative
tumor cells while protecting the wild type p53-containing normal cells from
drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-xL through negative regulation of NFκB activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative
cancer cells to anticancer drugs by separately affecting Bax and
Bcl-xL protein levels.