MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Abstract 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 accumu...

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Autores principales:	Vipin Shankar Chelakkot, Kaiwen Liu, Ema Yoshioka, Shaykat Saha, Danyang Xu, Maria Licursi, Ann Dorward, Kensuke Hirasawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/89d30e25a13d48b6bb300b1e717d98c2
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spelling	oai:doaj.org-article:89d30e25a13d48b6bb300b1e717d98c22021-12-02T11:57:57ZMEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes10.1038/s41598-020-79144-x2045-2322https://doaj.org/article/89d30e25a13d48b6bb300b1e717d98c22020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79144-xhttps://doaj.org/toc/2045-2322Abstract 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.Vipin Shankar ChelakkotKaiwen LiuEma YoshiokaShaykat SahaDanyang XuMaria LicursiAnn DorwardKensuke HirasawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vipin Shankar Chelakkot Kaiwen Liu Ema Yoshioka Shaykat Saha Danyang Xu Maria Licursi Ann Dorward Kensuke Hirasawa MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
description	Abstract 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.
format	article
author	Vipin Shankar Chelakkot Kaiwen Liu Ema Yoshioka Shaykat Saha Danyang Xu Maria Licursi Ann Dorward Kensuke Hirasawa
author_facet	Vipin Shankar Chelakkot Kaiwen Liu Ema Yoshioka Shaykat Saha Danyang Xu Maria Licursi Ann Dorward Kensuke Hirasawa
author_sort	Vipin Shankar Chelakkot
title	MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
title_short	MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
title_full	MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
title_fullStr	MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
title_full_unstemmed	MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes
title_sort	mek reduces cancer-specific ppix accumulation through the rsk-abcb1 and hif-1α-fech axes
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/89d30e25a13d48b6bb300b1e717d98c2
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MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

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