DAPK-HSF1 interaction as a new positive feedback loop for TNF-induced apoptosis in colorectal cancer cells

Abstract

Death-associated protein kinase (DAPK) is a serine-threonine kinase with tumor suppressor function. Previously, we demonstrated that tumor necrosis factor (TNF) induced DAPK-mediated apoptosis in colorectal cancer. However, the protein-protein interaction network associated with TNF-DAPK signaling still remains unclear. We identified HSF1 as a new DAPK phosphorylation target in response to low concentrations of TNF and verified a physical interaction between DAPK and HSF1 both in vitro and in vivo. We show that HSF1 binds to the DAPK promoter. Transient overexpression of HSF1 protein led to an increase in DAPK mRNA level and consequently to an increase in the amount of apoptosis. By contrast, treatment with a DAPK-specific inhibitor as well as DAPK knockdown abolished the phosphorylation of HSF1 at Ser230 (pHSF1 Ser230 ). Furthermore, translational studies demonstrated a positive correlation between DAPK and pHSF1 Ser230 protein expression in human colorectal carcinoma tissues. Taken together, our data define a novel link between DAPK and HSF1 and highlight a positive-feedback loop in DAPK regulation under mild inflammatory stress conditions in colorectal tumors. For the first time, we show that under TNF the pro-survival HSF1 protein can be redirected to a proapoptotic program.

Rethinking HSF1 in Stress, Development, and Organismal Health

“…However, there is now increasing evidence from a number of biological systems that HSF1 is important for diverse “non-stress” conditions including development [26, 40], energy metabolism [27], programmed cell death [41, 42] and carcinogenesis [28, 43]. For these non-heat shock conditions, the transcriptomes regulated by HSF1 are distinct from that of acute heat shock [26, 40].…”

Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review)

“…DAPK can be transcriptionally inhibited by the pro-inflammatory transcription factors STAT3 and NFκB ( 16 , 31 , 32 ). In addition, DAPK mRNA expression can be triggered by p53 ( 33 ), C/EBP-β ( 34 ), HSF1 ( 35 ), and SMAD ( 36 ). Whereas C/EBP-β binding depends on IFNγ exposure, the binding of SMAD to the corresponding motifs is triggered by TGF-β.…”

“…Of note, several studies reported that DAPK is crosslinked with TNF-receptor signaling and NF-κB activation providing further evidence for a potential therapeutic importance of DAPK in IBD. However, it was demonstrated that DAPK can process apparently opposing roles when either inhibiting or promoting inflammation ( 16 , 35 , 68 , 72 – 74 ). Thus, further analyses with careful characterization of cell type specific actions and context-dependent influences are needed before DAPK might be considered a therapeutic target candidate in IBD.…”

ADIPOQ rs266729 G/C gene polymorphism and plasmatic adipocytokines connect metabolic syndrome to colorectal cancer

“…This involves cytotoxic responses to tumors and a consequent increase in the carcinogenesis and metastasis 22, 23. Elevated plasma and tissue levels of TNF-α observed in obesity leading to the establishment of constant inflammatory state that increases the risk of colon cancer development 24, 25. APN is considered to have beneficial antineoplastic effects, which are believed to be due to anti-proliferative, anti-inflammatory effects, along with antagonizing insulin resistance 26.…”