Cargando…
Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells
Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346724/ https://www.ncbi.nlm.nih.gov/pubmed/27765904 http://dx.doi.org/10.18632/oncotarget.12712 |
_version_ | 1782513937565089792 |
---|---|
author | Zhen, Yun-fang Li, Song-tao Zhu, Yun-rong Wang, Xiao-dong Zhou, Xiao-zhong Zhu, Lun-qing |
author_facet | Zhen, Yun-fang Li, Song-tao Zhu, Yun-rong Wang, Xiao-dong Zhou, Xiao-zhong Zhu, Lun-qing |
author_sort | Zhen, Yun-fang |
collection | PubMed |
description | Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines). Further, forced-expression of microRNA-101 (“miR-101”) downregulated DNA-PKcs and augmented salinomycin's cytotoxicity against OS cells. Reversely, over-expression of DNA-PKcs in OS cells inhibited salinomycin's lethality. For the mechanism study, we show that DNA-PKcs is required for salinomycin-induced pro-survival autophagy activation. DNA-PKcs inhibition (by NU7441), shRNA knockdown or miR-101 expression inhibited salinomycin-induced Beclin-1 expression and autophagy induction. Meanwhile, knockdown of Beclin-1 by shRNA significantly sensitized salinomycin-induced OS cell lethality. In vivo, salinomycin administration suppressed U2OS xenograft tumor growth in severe combined immuno-deficient (SCID) mice, and its anti-tumor activity was dramatically potentiated with co-administration of the DNA-PKcs inhibitor NU7026. Together, these results suggest that DNA-PKcs could be a primary resistance factor of salinomycin in OS cells. DNA-PKcs inhibition or silence may thus significantly increase salinomycin's sensitivity in OS cells. |
format | Online Article Text |
id | pubmed-5346724 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53467242017-03-30 Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells Zhen, Yun-fang Li, Song-tao Zhu, Yun-rong Wang, Xiao-dong Zhou, Xiao-zhong Zhu, Lun-qing Oncotarget Research Paper Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines). Further, forced-expression of microRNA-101 (“miR-101”) downregulated DNA-PKcs and augmented salinomycin's cytotoxicity against OS cells. Reversely, over-expression of DNA-PKcs in OS cells inhibited salinomycin's lethality. For the mechanism study, we show that DNA-PKcs is required for salinomycin-induced pro-survival autophagy activation. DNA-PKcs inhibition (by NU7441), shRNA knockdown or miR-101 expression inhibited salinomycin-induced Beclin-1 expression and autophagy induction. Meanwhile, knockdown of Beclin-1 by shRNA significantly sensitized salinomycin-induced OS cell lethality. In vivo, salinomycin administration suppressed U2OS xenograft tumor growth in severe combined immuno-deficient (SCID) mice, and its anti-tumor activity was dramatically potentiated with co-administration of the DNA-PKcs inhibitor NU7026. Together, these results suggest that DNA-PKcs could be a primary resistance factor of salinomycin in OS cells. DNA-PKcs inhibition or silence may thus significantly increase salinomycin's sensitivity in OS cells. Impact Journals LLC 2016-10-17 /pmc/articles/PMC5346724/ /pubmed/27765904 http://dx.doi.org/10.18632/oncotarget.12712 Text en Copyright: © 2016 Zhen et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Zhen, Yun-fang Li, Song-tao Zhu, Yun-rong Wang, Xiao-dong Zhou, Xiao-zhong Zhu, Lun-qing Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title | Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title_full | Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title_fullStr | Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title_full_unstemmed | Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title_short | Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells |
title_sort | identification of dna-pkcs as a primary resistance factor of salinomycin in osteosarcoma cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346724/ https://www.ncbi.nlm.nih.gov/pubmed/27765904 http://dx.doi.org/10.18632/oncotarget.12712 |
work_keys_str_mv | AT zhenyunfang identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells AT lisongtao identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells AT zhuyunrong identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells AT wangxiaodong identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells AT zhouxiaozhong identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells AT zhulunqing identificationofdnapkcsasaprimaryresistancefactorofsalinomycininosteosarcomacells |