Cargando…

Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells

We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3, and 5...

Descripción completa

Detalles Bibliográficos
Autores principales: Yue, Peibin, Zhang, Xiaolei, Paladino, David, Sengupta, Bhaswati, Ahmad, Sarfraz, Holloway, Robert W., Ingersoll, Susan B., Turkson, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245777/
https://www.ncbi.nlm.nih.gov/pubmed/21909139
http://dx.doi.org/10.1038/onc.2011.409
_version_ 1782219893879341056
author Yue, Peibin
Zhang, Xiaolei
Paladino, David
Sengupta, Bhaswati
Ahmad, Sarfraz
Holloway, Robert W.
Ingersoll, Susan B.
Turkson, James
author_facet Yue, Peibin
Zhang, Xiaolei
Paladino, David
Sengupta, Bhaswati
Ahmad, Sarfraz
Holloway, Robert W.
Ingersoll, Susan B.
Turkson, James
author_sort Yue, Peibin
collection PubMed
description We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3, and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration, and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and Janus kinases (Jaks), aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF), and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility, and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared to the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small-intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer.
format Online
Article
Text
id pubmed-3245777
institution National Center for Biotechnology Information
language English
publishDate 2011
record_format MEDLINE/PubMed
spelling pubmed-32457772012-11-03 Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells Yue, Peibin Zhang, Xiaolei Paladino, David Sengupta, Bhaswati Ahmad, Sarfraz Holloway, Robert W. Ingersoll, Susan B. Turkson, James Oncogene Article We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3, and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration, and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and Janus kinases (Jaks), aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF), and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility, and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared to the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small-intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer. 2011-09-12 2012-05-03 /pmc/articles/PMC3245777/ /pubmed/21909139 http://dx.doi.org/10.1038/onc.2011.409 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Yue, Peibin
Zhang, Xiaolei
Paladino, David
Sengupta, Bhaswati
Ahmad, Sarfraz
Holloway, Robert W.
Ingersoll, Susan B.
Turkson, James
Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title_full Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title_fullStr Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title_full_unstemmed Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title_short Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
title_sort hyperactive egf receptor, jaks and stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245777/
https://www.ncbi.nlm.nih.gov/pubmed/21909139
http://dx.doi.org/10.1038/onc.2011.409
work_keys_str_mv AT yuepeibin hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT zhangxiaolei hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT paladinodavid hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT senguptabhaswati hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT ahmadsarfraz hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT hollowayrobertw hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT ingersollsusanb hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells
AT turksonjames hyperactiveegfreceptorjaksandstat3signalingpromoteenhancedcolonyformingabilitymotilityandmigrationofcisplatinresistantovariancancercells