Cargando…

Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying m...

Descripción completa

Detalles Bibliográficos
Autores principales: Lin, Zhoujun, Li, Yin, Han, Xiao, Fu, Zhenkun, Tian, Zhenhuan, Li, Chenggang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657307/
https://www.ncbi.nlm.nih.gov/pubmed/36361531
http://dx.doi.org/10.3390/ijms232112741
_version_ 1784829660879650816
author Lin, Zhoujun
Li, Yin
Han, Xiao
Fu, Zhenkun
Tian, Zhenhuan
Li, Chenggang
author_facet Lin, Zhoujun
Li, Yin
Han, Xiao
Fu, Zhenkun
Tian, Zhenhuan
Li, Chenggang
author_sort Lin, Zhoujun
collection PubMed
description Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying mechanism remains unclear. In the present study, we demonstrated the abnormal signature of SPHK1 in NSCLC lesions and cell lines of lung cancers with a potential tumorigenic role in cell cycle regulation. Functionally, ectopic Pre-B cell leukemia homeobox-1 (PBX1) was capable of restoring the arrested G1 phase induced by SPHK1 knockdown. However, exogenous sphingosine-1-phosphate (S1P) supply had little impact on the cell cycle arrest by PBX1 silence. Furthermore, S1P receptor S1PR3 was revealed as a specific switch to transport the extracellular S1P signal into cells, and subsequently activated PBX1 to regulate cell cycle progression. In addition, Akt signaling partially participated in the SPHK1/S1PR3/PBX1 axis to regulate the cell cycle, and the Akt inhibitor significantly decreased PBX1 expression and induced G1 arrest. Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment.
format Online
Article
Text
id pubmed-9657307
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96573072022-11-15 Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer Lin, Zhoujun Li, Yin Han, Xiao Fu, Zhenkun Tian, Zhenhuan Li, Chenggang Int J Mol Sci Article Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying mechanism remains unclear. In the present study, we demonstrated the abnormal signature of SPHK1 in NSCLC lesions and cell lines of lung cancers with a potential tumorigenic role in cell cycle regulation. Functionally, ectopic Pre-B cell leukemia homeobox-1 (PBX1) was capable of restoring the arrested G1 phase induced by SPHK1 knockdown. However, exogenous sphingosine-1-phosphate (S1P) supply had little impact on the cell cycle arrest by PBX1 silence. Furthermore, S1P receptor S1PR3 was revealed as a specific switch to transport the extracellular S1P signal into cells, and subsequently activated PBX1 to regulate cell cycle progression. In addition, Akt signaling partially participated in the SPHK1/S1PR3/PBX1 axis to regulate the cell cycle, and the Akt inhibitor significantly decreased PBX1 expression and induced G1 arrest. Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment. MDPI 2022-10-22 /pmc/articles/PMC9657307/ /pubmed/36361531 http://dx.doi.org/10.3390/ijms232112741 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lin, Zhoujun
Li, Yin
Han, Xiao
Fu, Zhenkun
Tian, Zhenhuan
Li, Chenggang
Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title_full Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title_fullStr Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title_full_unstemmed Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title_short Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer
title_sort targeting sphk1/pbx1 axis induced cell cycle arrest in non-small cell lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657307/
https://www.ncbi.nlm.nih.gov/pubmed/36361531
http://dx.doi.org/10.3390/ijms232112741
work_keys_str_mv AT linzhoujun targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer
AT liyin targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer
AT hanxiao targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer
AT fuzhenkun targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer
AT tianzhenhuan targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer
AT lichenggang targetingsphk1pbx1axisinducedcellcyclearrestinnonsmallcelllungcancer