title: Upregulation of DR5 receptor by the diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] triggers an independent extrinsic pathway of apoptosis in colon cancer cells with compromised pro and antiapoptotic proteins.
abstract: Mitochondria mediated signalling is the more common way of apoptosis induction exhibited by many chemotherapeutic agents in cancer cells. Death receptor mediated signalling for apoptosis in many cells also requires further amplification from the mitochondrial pathway activation through tBid. Thus the potential of most chemotherapeutic agents in tumours with intrinsic apoptosis resistance due to changes in molecules involved in the mitochondrial pathway is limited. Diaminothiazoles were shown earlier to bind to tubulin thereby exhibiting cytotoxicity towards different cancer cells. We observed that the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] could induce apoptosis in the colon cancer cell line HCT116 by both pathways. However, in contrast to many other chemotherapeutic agents, DAT1 triggered apoptosis where the intrinsic pathway was blocked by changing the pro and antiapoptotic proteins. An independent extrinsic pathway activation triggered by the upregulation of DR5 receptor accounted for that. The induction of DR5 occurred in the transcriptional level and the essential role of DR5 was confirmed by the fact that siRNA downregulation of DR5 significantly reduced DAT1 induced apoptosis. HCT116 cells were earlier shown to have a type II response for apoptosis induction where extrinsic pathway was connected to the intrinsic pathway via the mediator protein tBid. Our finding thus indicates that the signalling events in the manifestation of apoptosis depend not only on the cancer cell type, but also on the inducer. Our results also place diaminothiazoles in a promising position in the treatment of tumours with compromised apoptotic factors.
authors: Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Trivandrum 695014, India.
authors: Sannu A
authors: SA
authors: Thomas
authors: Smreti
authors: S
authors: Vasudevan
authors: Reshma
authors: R
authors: Thamkachy
authors: Swathi U
authors: SU
authors: Lekshmi
authors: Thankayyan R
authors: TR
authors: Santhoshkumar
authors: Kallikat N
authors: KN
authors: Rajasekharan
authors: Suparna
authors: S
authors: Sengupta
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D015843:Serpins / Q000494:pharmacology; D013844:Thiazoles; D014230:Triazoles / Q000494:pharmacology*; D015854:Up-Regulation; D014764:Viral Proteins / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: C496402:4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D015843:Serpins; D013844:Thiazoles; D014230:Triazoles; D014764:Viral Proteins; D051025:bcl-Associated Death Protein; C074641:interleukin-1beta-converting enzyme inhibitor; D053181:Caspase 8