Abstract
One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / metabolism
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Animals
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Apoptosis / drug effects*
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Biopsy
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Cannabinoids / pharmacology*
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Cell Cycle Proteins / metabolism
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Dronabinol / pharmacology*
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Endoplasmic Reticulum / metabolism
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Gene Expression Regulation, Neoplastic
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasms / metabolism*
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Neoplasms / pathology*
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Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / metabolism
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Signal Transduction
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Transcription Factor CHOP / metabolism
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Tumor Cells, Cultured
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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ATF4 protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Cannabinoids
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Cell Cycle Proteins
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DDIT3 protein, human
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NUPR1 protein, human
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Neoplasm Proteins
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Repressor Proteins
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TRIB3 protein, human
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Activating Transcription Factor 4
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Transcription Factor CHOP
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Dronabinol
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Protein Serine-Threonine Kinases