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.
View: Text | PDF
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

×

Figure 8

Proposed functional switch model of DAPK1 in p53-WT and p53-mutated breast cancer cells.

Options: View larger image (or click on image) Download as PowerPoint
Proposed functional switch model of DAPK1 in p53-WT and p53-mutated brea...
DAPK1 can be activated by various factors, such as cellular stress and growth signaling. In p53-WT cells, DAPK1 can activate p53, leading to p53 target gene transcription and apoptosis under death-related signaling. Simultaneously, DAPK1 can regulate cell growth by modulating TSC1/TSC2 complex formation in the mTOR pathway. Phosphorylation of TSC2 at Ser939 by DAPK1 reduces interaction between TSC1 and TSC2, leading to increased cell growth and protein synthesis and thereby maintaining a homeostatic balance between survival and death signaling. In contrast, DAPK1 expression is elevated in p53-mutant cells. The dysfunction of p53 in these cells prevents DAPK1 from inducing apoptosis, thereby resulting in a shift of function from apoptosis toward activation of the growth pathways. Therefore, in p53-mutated cells, suppression of DAPK1 strongly suppresses tumor cell growth.