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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

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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.

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Acknowledgments

The authors acknowledge Dr Julian Downward (London Research Institute) for the Bcl2 EGFP and BclXL EGFP plasmids, Dr Vishwa M. Dixit (University of California, SF) for the pcDNA3 CrmA plasmid and Dr Bert Vogelstein (Johns Hopkins School of Medicine) for the Bax deficient derivative of HCT116. The authors are also thankful for the financial support of R.G.C.B. core funding from Department of Biotechnology, Govt. of India and to the Council of Scientific and Industrial Research, Department of Biotechnology and University Grants Commission, Govt. of India for fellowships to Thomas, Vasudevan and Thamkachy respectively.

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The authors confirm that there are no conflicts of interest.

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Authors and Affiliations

  1. Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Trivandrum, 695014, India

    Sannu A. Thomas, Smreti Vasudevan, Reshma Thamkachy, Swathi U. Lekshmi, Thankayyan R. Santhoshkumar & Suparna Sengupta

  2. Department of Chemistry, University of Kerala, Trivandrum, India

    Kallikat N. Rajasekharan

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  1. Sannu A. Thomas
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Correspondence to Suparna Sengupta.

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Sannu A. Thomas, Smreti Vasudevan and Reshma Thamkachy contributed equally in the work.

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Thomas, S.A., Vasudevan, S., Thamkachy, R. et al. 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. Apoptosis 18, 713–726 (2013). https://doi.org/10.1007/s10495-013-0826-6

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