Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents

Abstract

The inactivation of the p53 tumor suppressor pathway in many cancers often increases their resistance to anticancer therapy. Here we show that a previously proposed strategy directed to Wip1 inhibition could be ineffective in tumors lacking p53. On the contrary, Wip1 overexpression sensitized these tumors to chemotherapeutic agents. This effect was mediated through interaction between Wip1 and RUNX2 that resulted, in response to anticancer treatment, in RUNX2-dependent transcriptional induction of the proapoptotic Bax protein. The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53. The overexpression of Wip1 in normal tissues provided protection from cisplatin-induced apoptosis through decreased strength of upstream signaling to p53. Thus, Wip1 phosphatase promotes apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.caspases | Bcl-2 family | dephosphorylation | intestine

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xLratio

“…26 We recently reported that elevated levels of Wip1 phosphatase increased the sensitivity of p53-negative tumor cells to chemotherapeutic agents through increasing the Bax/Bcl-x L ratio, a critical factor regulating execution of the apoptotic program. 27 Here, we provide additional evidence that Wip1 overexpression individually affects Bax and Bcl-x L levels by distinct mechanisms. These findings suggest that the biological properties of Wip1 as a stress-responsive phosphatase may provide the basis for improved anticancer therapy of p53-negative tumors.…”

“…Although we observed some reduction in Chk1 phosphorylation upon overexpression of Wip1, the Chk1-regulated G 2 /M checkpoint was not compromised, and the treated cells failed to reach mitosis. 27 Thus, under our experimental conditions, the increased dephosphorylation of Chk1 by Wip1 did not promote mitotic cell death.…”

“…To identify mechanisms leading to the increased sensitivity, we examined the expression levels of several pro-and anti-apoptotic proteins. 27 We noted that Bax protein levels were dramatically higher following cisplatin treatment in Wip1-overexpressing cells compared with control cells. 27 The best-characterized transcriptional factor inducing Bax transcription after the DNA damage is p53, 31 which is absent in Saos-2 cells.…”

“…27 We noted that Bax protein levels were dramatically higher following cisplatin treatment in Wip1-overexpressing cells compared with control cells. 27 The best-characterized transcriptional factor inducing Bax transcription after the DNA damage is p53, 31 which is absent in Saos-2 cells. It has been shown, however, that after Bone morphogenetic protein stimulation or etoposide treatment, Bax transcription was induced by another transcriptional factor, RUNX2.…”

Role of wild-type p53-induced phosphatase 1 in cancer

“…Conversely, previous studies have revealed that chemotherapy resistance induced by Wip1 is dependent on the presence of wild-type p53; however, in p53-negative cell lines, Wip1 sensitizes tumor cells to chemotherapeutic drugs by regulating the B-cell lymphoma-2 associated X protein:B-cell lymphoma-extra large ratio and runt related transcription factor-2 and protects normal tissues ( Fig. 1) (55,56). Therefore, Wip1 inhibition is a potential therapeutic target in bladder cancer with preserved wild-type p53, but the reverse effect may occur in p53-negative tumors; however, this remains to be elucidated.…”