KMID : 0620920150470020005
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Experimental & Molecular Medicine 2015 Volume.47 No. 2 p.5 ~ p.5
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¥â-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells
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Yi Yong-Weon
Kang Hyo-Jin Edward Jeong Bae Oh Seung-hoon Seong Yeon-Sun Bae In-soo
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Abstract
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An F-box protein, ¥â-TrCP recognizes substrate proteins and destabilizes them through ubiquitin-dependent proteolysis. It regulates the stability of diverse proteins and functions as either a tumor suppressor or an oncogene. Although the regulation by ¥â-TrCP has been widely studied, the regulation of ¥â-TrCP itself is not well understood yet. In this study, we found that the level of ¥â-TrCP1 is downregulated by various protein kinase inhibitors in triple-negative breast cancer (TNBC) cells. A PI3K/mTOR inhibitor PI-103 reduced the level of ¥â-TrCP1 in a wide range of TNBC cells in a proteasome-dependent manner. Concomitantly, the levels of c-Myc and cyclin E were also downregulated by PI-103. PI-103 reduced the phosphorylation of ¥â-TrCP1 prior to its degradation. In addition, knockdown of ¥â-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the ¥â-TrCP1 and c-Myc levels. These results suggest that mTORC2 regulates the stability of ¥â-TrCP1 in TNBC cells and targeting ¥â-TrCP1 is a potential approach to treat human TNBC.
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