Crocetin exploits p53-induced death domain (PIDD) and FAS-associated death domain (FADD) proteins to induce apoptosis in colorectal cancer.
Tumor suppressor p53 preserves the genomic integrity by restricting anomaly at the gene level. The hotspots for mutation in half of all colon cancers reside in p53. Hence, in a p53-mutated cellular milieu targeting cancer cells may be achievable by targeting the paralogue(s) of p53. Here we have shown the effectiveness of crocetin, a dietary component, in inducing apoptosis of colon cancer cells with varying p53 status. In wild-type p53-expressing cancer cells, p53 in one hand transactivates BAX and in parallel up-regulates p53-induced death domain protein (PIDD) that in turn cleaves and activates BID through caspase-2. Both BAX and t-BID converge at mitochondria to alter the transmembrane potential thereby leading to caspase-9 and caspase-3-mediated apoptosis. In contrast, in functional p53-impaired cells, this phytochemical exploits p53-paralogue p73, which up-regulates FAS to cleave BID through FAS-FADD-caspase-8-pathway. These findings not only underline the phenomenon of functional switch-over from p53 to p73 in p53-impaired condition, but also validate p73 as a promising and potential target for cancer therapy in absence of functional p53.
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Pallab
P
Ray
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Deblina
D
Guha
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Juni
J
Chakraborty
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Shuvomoy
S
Banerjee
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Arghya
A
Adhikary
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Samik
S
Chakraborty
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Tanya
T
Das
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700 054, India.
Gaurisankar
G
Sa
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D002338:Carotenoids / Q000627:therapeutic use*; D053143:Caspase 2 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D000072160:Tumor Protein p73 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014801:Vitamin A / Q000031:analogs & derivatives; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; C491901:FAS protein, human; D053200:Fas-Associated Death Domain Protein; C485896:PIDD1 protein, human; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; C490360:CASP2 protein, human; C505530:CASP8 protein, human; D053143:Caspase 2; D053181:Caspase 8; D003546:Cysteine Endopeptidases