PDF(Pubmed)
Abstract：
Tribbles pseudokinase 3 (TRIB3), a member of the mammalian Tribbles family, is implicated in multiple biological processes. This study aimed to investigate the biological functions of TRIB3 in lung cancer and its effect on amino acid-deprived lung cancer cells. TRIB3 mRNA expression was elevated in lung cancer tissues and cell lines compared to normal lung tissues and cells. TRIB3 knockdown markedly reduced the viability and proliferation of H1299 lung cancer cells. Deprivation of amino acids, particularly arginine, glutamine, lysine, or methionine, strongly increased TRIB3 expression via ATF4 activation in H1299 lung cancer cells. Knockdown of TRIB3 led to transcriptional downregulation of ATF4 and reduced AKT activation induced by amino acid deprivation, ultimately increasing the sensitivity of H1299 lung cancer cells to amino acid deprivation. Additionally, TRIB3 knockdown enhanced the sensitivity of H1299 cells to V-9302, a competitive antagonist of transmembrane glutamine flux. These results suggest that TRIB3 is a pro-survival regulator of cell viability in amino acid-deficient tumor microenvironments and a promising therapeutic target for lung cancer treatment.
摘要：
Tribbles假激酶3（TRIB3），哺乳动物Tribbles家族的一员,涉及多个生物过程。本研究旨在探讨TRIB3在肺癌中的生物学功能及其对缺乏氨基酸的肺癌细胞的影响。与正常肺组织和细胞相比，TRIB3mRNA在肺癌组织和细胞系中的表达升高。TRIB3敲低显著降低H1299肺癌细胞的活力和增殖。剥夺氨基酸，特别是精氨酸，谷氨酰胺,赖氨酸，或者蛋氨酸,在H1299肺癌细胞中通过ATF4激活强烈增加TRIB3表达。TRIB3的敲低导致ATF4的转录下调和氨基酸剥夺诱导的AKT激活减少,最终提高H1299肺癌细胞对氨基酸剥夺的敏感性。此外,TRIB3敲低增强了H1299细胞对跨膜谷氨酰胺通量的竞争性拮抗剂V-9302的敏感性。这些结果表明，TRIB3是氨基酸缺陷型肿瘤微环境中细胞活力的促存活调节剂，是肺癌治疗的有希望的治疗靶标。
