Death-associated protein kinase 1 promotes growth of p53-mutant cancers
Jing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, Powel H. Brown
Jing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, Powel H. Brown
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Research Article Oncology

Death-associated protein kinase 1 promotes growth of p53-mutant cancers

Abstract

Estrogen receptor–negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor–negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, DAPK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers.

Authors

Jing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, Powel H. Brown

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Figure 4

Suppression of DAPK1 expression inhibits the growth of p53-mutant breast cancer cells but not p53-WT MCF7 cells both in vitro and in vivo.

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Suppression of DAPK1 expression inhibits the growth of p53-mutant breast...
(A) Anchorage-dependent growth of p53-WT MCF7, p53-mutant MDAMB 231, HCC1143, and MDAMB 468 cells after DAPK1 suppression. Western blot was performed 3 times. A representative Western blot is shown. (B) Anchorage-independent growth of MCF7, MDAMB 231, MDAMB 468, and HCC1143 cells after DAPK1 suppression. (C) Effect of DAPK1 inhibitor on the growth of p53-WT and p53-mutant breast cancer cell lines. For each experiment, the DMSO concentration was 0.1% in all treatment groups for inhibitor- or vehicle-treated cells. For in vitro cell growth experiments (A–C), each data point represents 3 technical replicates, with results reported as average ± SEM. (D) In vivo xenograft growth of MCF7, MDAMB 231, and MDAMB 468 cells after DAPK1 suppression. (E) Effect of DAPK1 inhibitor on MDAMB 231 xenograft growth in vivo. For mouse xenograft experiments (D–E), 10 mice of each group were used and tumor growth rates were compared by linear regression of log-transformed tumor volumes over time. *P < 0.01; ***P < 0.0001, 2-tailed Student’s t test. See also Supplemental Figure 2.