Abstract
Abstract c-Myc is a helix-loop-helix leucine zipper transcription factor that has essential role in controlling many cell functions, including cell proliferation, differentiation, growth and apoptosis. However, c-Myc overexpression has been reported to occur in a majority of breast cancers and is associated with a poor prognosis. Apart from MYC gene amplification and translocation, it is also tightly regulated by signaling pathway that involves series of interdependent phosphorylation events. Myc stability is increased by phosphorylation at serine 62 (S62) by extracellular signal-regulated kinase (ERK) or cyclin dependent kinase (CDK), whereas subsequent phosphorylation at threonine T58 (T58) by glycogen synthase kinase b (GSK3 β) triggers dephosphorylation of S62 by protein phosphatase 2A-B56α (PP2A- B56α), leading to unbiquitination by SCF-Fbw7 E3 ligase and proteasomal degradation. Additionally, it has been shown that primary human breast cancer cells display increased levels of S62 Myc and decreased level of T58 Myc and mutations in this pathway result in accumulation of high level of oncogenic S62 Myc leading to tumorigenesis. γ-tocotrienol (γT3), a member of the vitamin E family has potent antiproliferative and apoptotic activity in a variety of cancer cell types at treatment doses that have little or no effect on normal cell viability or growth. Additionally, previous studies have shown that anti-proliferative dose of γT3 decreased c-Myc protein level in colorectal and pancreatic cancer cells. Therefore, studies were conducted to determine if γT3 decreases oncogenic S62 phosphorylation and triggers subsequent interdependent phosphorylation leading to c-Myc degradation in neoplastic mouse +SA and MCF-7 human epithelium mammary cancer cell lines. Treatment with 1-8μM γT3 resulted in a dose-responsive inhibition of +SA and MCF-7 breast cancer cell growth. Western blot analysis showed that antiproliferative dose of γ-tocotrienol resulted in a decrease in total c-Myc, phospho S62 Myc and increase in phospho T58 Myc in +SA and MCF-7 breast cancer cells. Further studies showed that similar doses decreased phosphorylated (activated) Akt and its downstream targets GSK-3β and mTOR, as well as phosphorylated (activated) 44/41 MAPK or (Erk 1/2). Additional studies showed that the antiproliferative effects of γT3 were also associated with a decrease in cyclin D1 and cyclin dependent kinase 4 (CDK4). Western blot analysis has also shown an increase in FBw7, an E3 ligase that initiates ubiquitination of c-Myc. However, no change in protein phosphatase 2A (PP2A) and Pin 1 prolyl isomerase was observed in +SA and MCF-7 mammary cancer cells. In summary, these findings demonstrate that the antiproliferative effects of γ-tocotrienol are mediated, at least in part, by decreasing oncogenic c-Myc (S62) levels and a corresponding reduction in Akt/mTOR and MAPK signaling. These effects were also associated with an increase in GSK-3β-induced phosphorylation of T58 and the promotion of the ubiquitination and degradation of c-Myc. This study was supported by grants from First Tech International Ltd., and the Malaysian Palm Oil Council. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-03-09.
Published Version
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