dc.contributor.author |
Silva, Jillian M |
en |
dc.contributor.author |
Deuker, Marian M |
en |
dc.contributor.author |
Baguley, Bruce |
en |
dc.contributor.author |
McMahon, Martin |
en |
dc.date.accessioned |
2018-10-18T01:57:42Z |
en |
dc.date.issued |
2017-05 |
en |
dc.identifier.issn |
1755-1471 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/42825 |
en |
dc.description.abstract |
Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3'-lipid signaling. However, the mechanism by which PI3'-lipid signaling cooperates with mutationally activated BRAF or NRAS has not been adequately explored. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3'-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and antiproliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent antiproliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRASQ61H /PIK3CAH1047R melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Pigment cell & melanoma research |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line, Tumor |
en |
dc.subject |
Animals |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice, Nude |
en |
dc.subject |
Melanoma |
en |
dc.subject |
Proto-Oncogene Proteins B-raf |
en |
dc.subject |
Mitogen-Activated Protein Kinase Kinases |
en |
dc.subject |
Protein Kinase Inhibitors |
en |
dc.subject |
Xenograft Model Antitumor Assays |
en |
dc.subject |
Signal Transduction |
en |
dc.subject |
Cell Proliferation |
en |
dc.subject |
Drug Resistance, Neoplasm |
en |
dc.subject |
Mutation |
en |
dc.subject |
Class I Phosphatidylinositol 3-Kinases |
en |
dc.subject |
Carcinogenesis |
en |
dc.subject |
Mechanistic Target of Rapamycin Complex 1 |
en |
dc.subject |
Mechanistic Target of Rapamycin Complex 2 |
en |
dc.title |
PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1111/pcmr.12586 |
en |
pubs.issue |
3 |
en |
pubs.begin-page |
353 |
en |
pubs.volume |
30 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
28233937 |
en |
pubs.end-page |
367 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.subtype |
Research Support, N.I.H., Extramural |
en |
pubs.elements-id |
615966 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1755-148X |
en |
pubs.record-created-at-source-date |
2017-02-25 |
en |
pubs.dimensions-id |
28233937 |
en |