Abstract
Overexpression of Shc adaptor proteins is associated with mitogenesis, carcinogenesis and metastasis. Multiple copies in T-cell malignancy 1 (MCT-1) oncoprotein promotes cell proliferation, survival and tumorigenic effects. Our current data show that MCT-1 is a novel regulator of Shc-Ras-MEK-ERK signaling and MCT-1 is significantly co-activated with Shc gene in human carcinomas. The knockdown of MCT-1 enhances apoptotic cell death accompanied with the activation of caspases and cleavage of caspase substrates under environmental stress. The cancer cell proliferation, chemo-resistance and tumorigenic capacity are proved to be effectively suppressed by targeting MCT-1. Accordingly, an important linkage between MCT-1 oncogenicity and Shc pathway in tumor development has now been established. Promoting MCT-1 expression by gene hyperactivation may be recognized as a tumor marker and MCT-1 may serve as a molecular target of cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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Caspase 3 / metabolism
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Female
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Gene Knockdown Techniques
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Humans
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Immunohistochemistry
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Integrin beta4 / metabolism
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy
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MAP Kinase Signaling System
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Oncogene Proteins / antagonists & inhibitors*
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Oncogene Proteins / biosynthesis
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Paclitaxel / pharmacology
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Poly(ADP-ribose) Polymerases / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Shc Signaling Adaptor Proteins / antagonists & inhibitors*
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Shc Signaling Adaptor Proteins / biosynthesis
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Shc Signaling Adaptor Proteins / genetics
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Shc Signaling Adaptor Proteins / metabolism
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Transfection
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Xenograft Model Antitumor Assays
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ras Proteins / metabolism
Substances
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Cell Cycle Proteins
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Integrin beta4
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MCTS1 protein, human
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Oncogene Proteins
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RNA, Messenger
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Shc Signaling Adaptor Proteins
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Poly(ADP-ribose) Polymerases
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Caspase 3
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ras Proteins
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Paclitaxel