DAPK-HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells.
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 pro-apoptotic program.
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Natalya
N
Benderska
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Jelena
J
Ivanovska
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Tilman T
TT
Rau
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Jan
J
Schulze-Luehrmann
Faculty of School of Chemical & Biotechnology of the SASTRA University, Thanjavur 613401, India.
Suma
S
Mohan
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Saritha
S
Chakilam
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Muktheshwar
M
Gandesiri
3rd Medical Department, Medical University, 55122 Mainz, Germany.
Elisabeth
E
Ziesché
Center of Internal Medicine, Clinic of Hematology/Oncology, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
Thomas
T
Fischer
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Stephan
S
Söder
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Abbas
A
Agaimy
Department of Radiation Oncology, University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Luitpold
L
Distel
Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
Heinrich
H
Sticht
Faculty of School of Chemical & Biotechnology of the SASTRA University, Thanjavur 613401, India.
Vijayalakshmi
V
Mahadevan
Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany regine.schneider-stock@uk-erlangen.de.
Regine
R
Schneider-Stock
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D064550:Death-Associated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; D064550:Death-Associated Protein Kinases
Apoptosis; Cancer; Colon; DAPK; HSF1; TNF