title: Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways.
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.
authors: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Road, Scheme VII M, Kolkata, West Bengal, 700 054, India.
authors: Minakshi
authors: M
authors: Mazumdar
authors: Arghya
authors: A
authors: Adhikary
authors: Samik
authors: S
authors: Chakraborty
authors: Shravanti
authors: S
authors: Mukherjee
authors: Argha
authors: A
authors: Manna
authors: Shilpi
authors: S
authors: Saha
authors: Suchismita
authors: S
authors: Mohanty
authors: Amrita
authors: A
authors: Dutta
authors: Pushpak
authors: P
authors: Bhattacharjee
authors: Pallab
authors: P
authors: Ray
authors: Sreya
authors: S
authors: Chattopadhyay
authors: Shuvomoy
authors: S
authors: Banerjee
authors: Juni
authors: J
authors: Chakraborty
authors: Arun K
authors: AK
authors: Ray
authors: Gaurisankar
authors: G
authors: Sa
authors: Tanya
authors: T
authors: Das
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D044946:Biflavonoids / Q000494:pharmacology; D018278:Carcinoma, Neuroendocrine; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D018076:DNA, Complementary; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494819:BAD protein, human; D044946:Biflavonoids; D018076:DNA, Complementary; D051025:bcl-Associated Death Protein; C056068:theaflavin; D002392:Catechin; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; D015689:Oncogene Protein p21(ras)