Division of Medical Sciences, BK21 Plus program, Graduate School of Ajou University, Suwon, 16499, Republic of Korea.
Department of Pathology, Chung-Ang University College of Medicine, Seoul, 156-756, Republic of Korea.
J Cancer Res Clin Oncol. 2018 Aug;144(8):1445-1462. doi: 10.1007/s00432-018-2677-6. Epub 2018 May 28.
It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity.
Transduction of adenovirus carrying TIS21 gene and transfection of short interfering RNAs were employed to regulate TIS21 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21 expression in various human breast cancer tissues.
We observed that TIS21 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21-induced pAKT required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21 gene. Additionally, the TIS21-induced pAKT could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment.
TIS21 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21-mTORc2-AKT1-NFAT1-PHLPP2 pathway.
据报道，PI3K/AKT 通路在各种癌症中发生改变，AKT 同工型特异性调节癌细胞的生长和转移；AKT1 而非 AKT2 降低癌细胞的侵袭，但维持癌细胞的生长。我们在此提出了一种新型肿瘤抑制因子 TIS21 的作用机制，通过差异调节 mTORc1 和 mTORc2 的活性，激活 AKT1，从而抑制三阴性乳腺癌细胞的生长和侵袭。
采用携带 TIS21 基因的腺病毒转导和短干扰 RNA 转染来调节各种细胞系中的 TIS21 基因表达。用 mTOR 抑制剂处理和 mTOR 激酶测定可以评估 TIS21 在乳腺癌细胞中调节 AKT 在 S473 残基磷酸化的作用中 mTORc 的作用。开放数据和免疫组织化学分析用于证实 TIS21 表达在各种人乳腺癌组织中的作用。
我们观察到 TIS21 通过减少 Raptor-mTOR 相互作用并上调 tsc1 表达来抑制 mTORc1 活性，这导致 p70S6K 的激活显著减少，而 AKT1 磷酸化，而非 AKT2，通过下调 AKT1 特异性磷酸酶 PHLPP2 来减少。TIS21 诱导的 pAKT 需要 Rictor 结合的 mTOR 激酶，表明 TIS21 基因激活 mTORc2。此外，TIS21 诱导的 pAKT 可降低 NFAT1（激活 T 细胞的核因子）及其靶基因的表达，从而调节癌症微环境。
TIS21 在浸润性导管癌中显著丢失，但它可以通过 TIS21-tsc1/2-mTORc1-p70S6K 轴抑制癌症生长，并通过 TIS21-mTORc2-AKT1-NFAT1-PHLPP2 途径下调癌症进展。
