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Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways

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Abstract

Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate RET as a promising and potential target for MTC therapy.

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Abbreviations

cDNA:

Complementary deoxyribonucleic acid

ERK:

Extracellular signal-regulated protein kinases

IB:

Immunoblotting

IP:

Immunoprecipitation

MEN 2:

Multiple endocrine neoplasia type 2

MTC:

Medullary thyroid cancer

p38MAPK:

p38 Mitogen-activated protein kinase

RET:

REarranged during Transfection

siRNA:

Short-interfering RNA

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Acknowledgments

Authors are thankful to Ms. R. Sarkar for editing the manuscript. Thanks are also due to Mr. R. Dutta, Mr. S. Samanta, Mrs. S. Das for technical help. This work was supported by research grants from Department of Biotechnology, Department of Science and Technology, Council of Scientific and Industrial Research, Government of India.

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  1. Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Road, Scheme VII M, Kolkata, West Bengal, 700 054, India

    Minakshi Mazumdar, Arghya Adhikary, Samik Chakraborty, Shravanti Mukherjee, Argha Manna, Shilpi Saha, Suchismita Mohanty, Amrita Dutta, Pushpak Bhattacharjee, Pallab Ray, Sreya Chattopadhyay, Shuvomoy Banerjee, Juni Chakraborty, Arun K. Ray, Gaurisankar Sa & Tanya Das

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  1. Minakshi Mazumdar
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Correspondence to Tanya Das.

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Minakshi Mazumdar and Arghya Adhikary contributed equally to this work.

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Mazumdar, M., Adhikary, A., Chakraborty, S. et al. Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways. Apoptosis 18, 589–604 (2013). https://doi.org/10.1007/s10495-013-0803-0

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