MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes.
MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes.
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MEK通过RSK-ABCB1和HIF-1α-Fech轴减少了癌症特异性PPIX的积累。
DOI：
10.1038/s41598-020-79144-x
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发表时间：
2020-12-17
影响因子：
4.6
通讯作者：
Hirasawa K
中科院分区：
文献类型：
--
作者：
Chelakkot VS;Liu K;Yoshioka E;Saha S;Xu D;Licursi M;Dorward A;Hirasawa K
基于氨基酮戊酸(5-ALA)的光动力学诊断(5-ALA-PDD)和光动力疗法(5-ALA-PDT)的疗效依赖于5-ALA诱导的癌特异性原卟啉IX(PpIX)积聚。我们以前曾报道，抑制致癌的RAS/MEK通过减少PpIX通过三磷酸腺苷结合盒B亚家族成员1(ABCB1)和铁络合酶(FECH)催化的PpIX转化为Hem而减少PpIX在癌细胞中的积聚。在这里，我们试图确定RAS/MEK的下游通路，通过ABCB1和FECH参与调节PpIX的积累。首先，我们证明了Ras/MEK的激活减少了PpIX在RasV12转化的NIH3T3细胞和HRAS转基因小鼠中的积累。P90核糖体S6激酶(RSK)2、3或4的敲除可增加RasV12转化的NIH3T3细胞中PpIX的积聚。此外，用RSK抑制剂治疗减少了ABCB1的表达，增加了PpIX的积累。此外，在RasV12转化的NIH3T3细胞中加入甲硫氨酸蛋白激酶抑制剂后，缺氧诱导因子-1α的表达明显降低，说明缺氧诱导因子-1α是甲硫氨酸蛋白激酶的下游元件。抑制HIF-1FECH活性，增加α积累量。最后，我们证明了RSKs和HIF-1α参与了PPIx在人类癌细胞系中积累的调控。这些结果表明，Ras-ABCB1和HIF-1Ras-α-FECH轴是Ras/MEK的下游途径，参与了Ppix的积累调控。
The efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and photodynamic therapy (5-ALA-PDT) is dependent on 5-ALA-induced cancer-specific accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding cassette sub-family B member 1 (ABCB1) and ferrochelatase (FECH)-catalysed PpIX conversion to haem. Here, we sought to identify the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a downstream element of MEK. HIF-1α inhibition decreased FECH activity and increased PpIX accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of PpIX accumulation in human cancer cell lines. These results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation.
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DOI：
10.3322/caac.20114
发表时间：
2011-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Agostinis P;Berg K;Cengel KA;Foster TH;Girotti AW;Gollnick SO;Hahn SM;Hamblin MR;Juzeniene A;Kessel D;Korbelik M;Moan J;Mroz P;Nowis D;Piette J;Wilson BC;Golab J
通讯作者：
Golab J
影响因子：
8.8
作者：
Li, G;Szewczuk, MR;Raptis, L;Johnson, JG;Weagle, GE;Pottier, RH;Kennedy, JC
通讯作者：
Kennedy, JC
影响因子：
8.8
作者：
Chelakkot, Vipin Shankar;Som, Jayoti;Hirasawa, Kensuke
通讯作者：
Hirasawa, Kensuke
DOI：
10.1073/pnas.95.21.12202
发表时间：
1998-10-13
影响因子：
11.1
作者：
De Cesare, D;Jacquot, S;Sassone-Corsi, P
通讯作者：
Sassone-Corsi, P
影响因子：
3.9
作者：
Heinemann, Ilka U.;Jahn, Martina;Jahn, Dieter
通讯作者：
Jahn, Dieter