Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.

Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib resistance (ER) in non-small cell lung cancer is being recognized as a major problem. Therefore, unde...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jasmine G Lee, Reen Wu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/10617858532e444492e98bbf859e0d62
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:10617858532e444492e98bbf859e0d62
record_format	dspace
spelling	oai:doaj.org-article:10617858532e444492e98bbf859e0d622021-11-18T08:10:21ZCombination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.1932-620310.1371/journal.pone.0048532https://doaj.org/article/10617858532e444492e98bbf859e0d622012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23119048/?tool=EBIhttps://doaj.org/toc/1932-6203Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib resistance (ER) in non-small cell lung cancer is being recognized as a major problem. Therefore, understanding the mechanism behind ER and developing effective regimens are needed. Autophagy's role in cancer has been controversial and remains unclear. In this study, we examined the effectiveness of low dose erlotinib-cisplatin combination in erlotinib resistant lung adenocarcinoma (ERPC9) cells and the role of autophagy in ER. ERPC9 cells were established from erlotinib sensitive PC9 cells. Appropriate treatments were done over two days and cell survival was quantified with Alamar Blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA) was utilized to inhibit translation of the protein of interest. In ERPC9 cells, combination treatment induced synergistic cell death and a significant decrease in autophagy. At baseline, ERPC9 cells had a significantly higher LC3II and lower p-mTOR levels compared to PC9 cells. The addition of rapamycin increased resistance and 3-methyladenine sensitized ERPC9 cells, indicating autophagy may be acting as a protective mechanism. Further examination revealed that ERPC9 cells harbored high baseline Atg3 levels. The high basal Atg3 was targeted and significantly lowered with combination treatment. siRNA transfection of Atg3 resulted in the reversal of ER; 42.0% more cells died in erlotinib-alone treatment with transfection compared to non-transfected ERPC9 cells. We reveal a novel role for Atg3 in the promotion of ER as the inhibition of Atg3 translation was able to result in the re-sensitization of ERPC9 cells to erlotinib-alone treatment. Also, we demonstrate that combination erlotinib-cisplatin is an effective treatment against erlotinib resistant cancer by targeting (down-regulating) Atg3 mediated autophagy and induction of apoptotic cell death.Jasmine G LeeReen WuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e48532 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jasmine G Lee Reen Wu Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
description	Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib resistance (ER) in non-small cell lung cancer is being recognized as a major problem. Therefore, understanding the mechanism behind ER and developing effective regimens are needed. Autophagy's role in cancer has been controversial and remains unclear. In this study, we examined the effectiveness of low dose erlotinib-cisplatin combination in erlotinib resistant lung adenocarcinoma (ERPC9) cells and the role of autophagy in ER. ERPC9 cells were established from erlotinib sensitive PC9 cells. Appropriate treatments were done over two days and cell survival was quantified with Alamar Blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA) was utilized to inhibit translation of the protein of interest. In ERPC9 cells, combination treatment induced synergistic cell death and a significant decrease in autophagy. At baseline, ERPC9 cells had a significantly higher LC3II and lower p-mTOR levels compared to PC9 cells. The addition of rapamycin increased resistance and 3-methyladenine sensitized ERPC9 cells, indicating autophagy may be acting as a protective mechanism. Further examination revealed that ERPC9 cells harbored high baseline Atg3 levels. The high basal Atg3 was targeted and significantly lowered with combination treatment. siRNA transfection of Atg3 resulted in the reversal of ER; 42.0% more cells died in erlotinib-alone treatment with transfection compared to non-transfected ERPC9 cells. We reveal a novel role for Atg3 in the promotion of ER as the inhibition of Atg3 translation was able to result in the re-sensitization of ERPC9 cells to erlotinib-alone treatment. Also, we demonstrate that combination erlotinib-cisplatin is an effective treatment against erlotinib resistant cancer by targeting (down-regulating) Atg3 mediated autophagy and induction of apoptotic cell death.
format	article
author	Jasmine G Lee Reen Wu
author_facet	Jasmine G Lee Reen Wu
author_sort	Jasmine G Lee
title	Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
title_short	Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
title_full	Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
title_fullStr	Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
title_full_unstemmed	Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.
title_sort	combination erlotinib-cisplatin and atg3-mediated autophagy in erlotinib resistant lung cancer.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/10617858532e444492e98bbf859e0d62
work_keys_str_mv	AT jasmineglee combinationerlotinibcisplatinandatg3mediatedautophagyinerlotinibresistantlungcancer AT reenwu combinationerlotinibcisplatinandatg3mediatedautophagyinerlotinibresistantlungcancer
_version_	1718422090363699200

Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.

Ejemplares similares