γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents.

Abstract

Although γ-tocotrienol (T3), a vitamin E isolated primarily from palm and rice bran oil, has been linked with anticancer activities, the mechanism of this action is poorly understood. In this study, we investigated whether γ-T3 can modulate the STAT3 cell signaling pathway, closely linked to inflammation and tumorigenesis. We found that γ-T3 but not γ-tocopherol, the most common saturated form of vitamin E, inhibited constitutive activation of STAT3 in a dose- and time-dependent manner, and this inhibition was not cell type-specific. γ-T3 also inhibited STAT3 DNA binding. This correlated with inhibition of Src kinase and JAK1 and JAK2 kinases. Pervanadate reversed the γ-T3-induced down-regulation of STAT3 activation, suggesting the involvement of a protein-tyrosine phosphatase. When examined further, we found that γ-T3 induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of γ-T3 to inhibit STAT3 activation, suggesting a vital role for SHP-1 in the action of γ-T3. Also γ-T3 down-modulated activation of STAT3 and induced SHP-1 in vivo. Eventually, γ-T3 down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of the cell cycle, and induction of apoptosis. This vitamin also sensitized the tumor cells to the apoptotic effects of thalidomide and bortezomib. Overall, our results suggest that γ-T3 is a novel blocker of STAT3 activation pathway both in vitro and in vivo and thus may have potential in prevention and treatment of cancers.

• Authors: Ramaswamy Kannappan, Vivek R Yadav, Bharat B Aggarwal
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 43 Pg. 33520-33529 (Oct 22 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20720018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Antioxidants
• Boronic Acids
• Chromans
• Inhibitor of Apoptosis Proteins
• Neoplasm Proteins
• Pyrazines
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• Vitamin E
• plastochromanol 8
• Thalidomide
• Bortezomib
• gamma-Tocopherol
• JAK1 protein, human
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2
• src-Family Kinases
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis
• Boronic Acids (pharmacology)
• Bortezomib
• Chromans (pharmacology)
• Enzyme Induction (drug effects)
• G1 Phase (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Gene Silencing
• Humans
• Inhibitor of Apoptosis Proteins (biosynthesis, genetics)
• Janus Kinase 1 (genetics, metabolism)
• Janus Kinase 2 (genetics, metabolism)
• Mice
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms (drug therapy, genetics, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (biosynthesis, genetics)
• Pyrazines (pharmacology)
• RNA, Small Interfering
• STAT3 Transcription Factor (genetics, metabolism)
• Thalidomide (pharmacology)
• Vitamin E (analogs & derivatives, pharmacology)
• gamma-Tocopherol (pharmacology)
• src-Family Kinases (genetics, metabolism)