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 Mills, Powel H. Brown

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2707-2720
Number of pages14
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Death-Associated Protein Kinases
Growth
Neoplasms
Breast Neoplasms
Triple Negative Breast Neoplasms
Pancreatic Neoplasms
Estrogen Receptors
Ovarian Neoplasms
Carcinogenesis
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhao, J., Zhao, D., Poage, G. M., Mazumdar, A., Zhang, Y., Hill, J. L., ... Brown, P. H. (2015). Death-associated protein kinase 1 promotes growth of p53-mutant cancers. Journal of Clinical Investigation, 125(7), 2707-2720. https://doi.org/10.1172/JCI70805

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

In: Journal of Clinical Investigation, Vol. 125, No. 7, 01.01.2015, p. 2707-2720.

Research output: Contribution to journalArticle

Zhao, J, Zhao, D, Poage, GM, Mazumdar, A, Zhang, Y, Hill, JL, Hartman, ZC, Savage, MI, Mills, G & Brown, PH 2015, 'Death-associated protein kinase 1 promotes growth of p53-mutant cancers', Journal of Clinical Investigation, vol. 125, no. 7, pp. 2707-2720. https://doi.org/10.1172/JCI70805
Zhao J, Zhao D, Poage GM, Mazumdar A, Zhang Y, Hill JL et al. Death-associated protein kinase 1 promotes growth of p53-mutant cancers. Journal of Clinical Investigation. 2015 Jan 1;125(7):2707-2720. https://doi.org/10.1172/JCI70805
Zhao, Jing ; Zhao, Dekuang ; Poage, Graham M. ; Mazumdar, Abhijit ; Zhang, Yun ; Hill, Jamal L. ; Hartman, Zachary C. ; Savage, Michelle I. ; Mills, Gordon ; Brown, Powel H. / Death-associated protein kinase 1 promotes growth of p53-mutant cancers. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 7. pp. 2707-2720.
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