Page 32 - H. Cell signaling

[H. Cell signaling-25]

Role of mTORC2 in NK cell-mediated cytotoxicity against

tumor cells

Jaeho Cho¹, Mirae Kim¹, Gyu Tae Park¹, Sung Su Yea¹

¹Dept. of Biochemistry, Inje University College of Medicine, Busan 47392, Korea

Recently, isoform-specific inhibitors of phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR)
are being evaluated for their therapeutic potential in cancer. However, little is known about their roles in natural
killer (NK) cell. Here we assessed how different classes of PI3K inhibitors and mTOR complex (mTORC) inhibitors

affect the function of NK cells. Inhibitors of all class I PI3K isoforms significantly impaired cell-mediated cytotoxicity

(CMC) of NK cells against tumor cells, whereas isoform-selective inhibitors had little effect. CMC of NK cells against
tumor cells was down-regulated by PP242, an inhibitor for both complex of mTOR, but not by rapamycin inhibiting
mTORC1 only. To study the role of mTORC2 on NK CMC, we evaluated the effect of knocking down RICTOR, a

critical factor for mTORC2. RICTOR knocked down found to inhibit NK CMC against tumor cells. In addition,
regulation of AKT, a downstream kinase of mTORC2, using siRNA as well as selective inhibitor also resulted in down-

regulation of NK CMC against tumor cells. These results reveal the mTORC2 is important for NK cell functions and
indicate that isoform-selective regulation would provide a better therapeutic window for specific disease states than

achieved by targeting all isoforms.