Death-associated protein kinase 1 promotes growth of p53-mutant cancers
Jing Zhao, … , Gordon B. Mills, Powel H. Brown
Jing Zhao, … , Gordon B. Mills, Powel H. Brown
Published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2707-2720. https://doi.org/10.1172/JCI70805.
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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 3

p53 depletion sensitizes p53-WT breast cancer cells to DAPK1 knockdown.

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p53 depletion sensitizes p53-WT breast cancer cells to DAPK1 knockdown. ...
(A) Experimental design. In order to determine whether p53 status is relevant to cell line sensitivity to DAPK1 knockdown, we depleted p53 expression in 2 p53-WT cell lines (MCF7 and ZR-75-1) by constitutively expressing shRNA and comparing sensitivity to DAPK1 knockdown. (B) Shown is p53 protein expression in p53-WT and p53-depleted MCF7 (left panel) and ZR-75-1 (right panel) cells. (C) DAPK1 expression in p53-WT and p53-depleted ZR-75-1 cells. Western blot experiments were performed 3 times, and representative blots are shown. (D) Growth of MCF7 control (left panel) and MCF7 sh-p53 (MCF7 with p53 depleted; right panel) cells upon DAPK1 knockdown by siRNA. (E) Growth of ZR-75-1 control (left panel) and ZR-75-1 sh-p53 (ZR-75-1 with p53 depleted; right panel) upon DAPK1 knockdown by siRNA. DAPK1 knockdown and cell growth experiments were performed in triplicate, with results reported as average ± SEM. *P < 0.01; **P < 0.001, 2-tailed Student’s t test. sh-ctrl, MCF7 and ZR-75-1 cells transfected with empty vector; sh-p53, MCF7 and ZR-75-1 cells transfected with shRNA against p53 to make these cells p53 deficient.