Varlı Mücahit, Kim Sung Jin, Noh Myung-Giun, Kim Yoon Gyoon, Ha Hyung-Ho, Kim Kyung Keun, Kim Hangun
College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea.
Department of Pharmacology, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Gwangju, 61469, Republic of Korea.
Cell Biosci. 2023 Aug 8;13(1):146. doi: 10.1186/s13578-023-01089-1.
The oncoprotein KAI1 C-terminal interacting tetraspanin (KITENIN; vang-like 1) promotes cell metastasis, invasion, and angiogenesis, resulting in shorter survival times in cancer patients. Here, we aimed to determine the effects of KITENIN on the energy metabolism of human colorectal cancer cells.
The effects of KITENIN on energy metabolism were evaluated using in vitro assays. The GEPIA web tool was used to extrapolate the clinical relevance of KITENIN in cancer cell metabolism. The bioavailability and effect of the disintegrator of KITENIN complex compounds were evaluated by LC-MS, in vivo animal assay.
KITENIN markedly upregulated the glycolytic proton efflux rate and aerobic glycolysis by increasing the expression of GLUT1, HK2, PKM2, and LDHA. β-catenin, CD44, CyclinD1 and HIF-1A, including c-Myc, were upregulated by KITENIN expression. In addition, KITENIN promoted nuclear PKM2 and PKM2-induced transactivation, which in turn, increased the expression of downstream mediators. This was found to be mediated through an effect of c-Myc on the transcription of hnRNP isoforms and a switch to the M2 isoform of pyruvate kinase, which increased aerobic glycolysis. The disintegration of KITENIN complex by silencing the KITENIN or MYO1D downregulated aerobic glycolysis. The disintegrator of KITENIN complex compound DKC1125 and its optimized form, DKC-C14S, exhibited the inhibition activity of KITENIN-mediated aerobic glycolysis in vitro and in vivo.
The oncoprotein KITENIN induces PKM2-mediated aerobic glycolysis by upregulating the c-Myc/hnRNPs axis.
癌蛋白KAI1 C端相互作用四跨膜蛋白（KITENIN；类vang蛋白1）促进细胞转移、侵袭和血管生成，导致癌症患者生存时间缩短。在此，我们旨在确定KITENIN对人结肠癌细胞能量代谢的影响。
使用体外试验评估KITENIN对能量代谢的影响。利用GEPIA网络工具推断KITENIN在癌细胞代谢中的临床相关性。通过液相色谱-质谱联用仪（LC-MS）、体内动物试验评估KITENIN复合化合物分解剂的生物利用度和效果。
KITENIN通过增加葡萄糖转运蛋白1（GLUT1）、己糖激酶2（HK2）、丙酮酸激酶M2型（PKM2）和乳酸脱氢酶A（LDHA）的表达，显著上调糖酵解质子外流率和有氧糖酵解。KITENIN的表达上调了β-连环蛋白、CD44、细胞周期蛋白D1和低氧诱导因子1α（HIF-1A），包括c-Myc。此外，KITENIN促进核PKM2和PKM2诱导的反式激活，进而增加下游介质的表达。发现这是通过c-Myc对不均一核糖核蛋白（hnRNP）亚型转录的影响以及向丙酮酸激酶M2亚型的转变介导的，这增加了有氧糖酵解。通过沉默KITENIN或肌球蛋白1D（MYO1D）使KITENIN复合物解体，下调了有氧糖酵解。KITENIN复合化合物DKC1125及其优化形式DKC-C14S的分解剂在体外和体内均表现出对KITENIN介导的有氧糖酵解的抑制活性。
癌蛋白KITENIN通过上调c-Myc/hnRNPs轴诱导PKM2介导的有氧糖酵解。
