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PMID: 21317224 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression.

Cancer research ·Vol. 71 ·No. 7 ·2011-04-01 ·Pages 2750-60

Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS

Abstract

This study addresses the role of PTEN loss in intrinsic resistance to the BRAF inhibitor PLX4720. Immunohistochemical staining of a tissue array covering all stages of melanocytic neoplasia (n = 192) revealed PTEN expression to be lost in >10% of all melanoma cases. Although PTEN expression status did not predict for sensitivity to the growth inhibitory effects of PLX4720, it was predictive for apoptosis, with only limited cell death observed in melanomas lacking PTEN expression (PTEN-). Mechanistically, PLX4720 was found to stimulate AKT signaling in the PTEN- but not the PTEN+ cell lines. Liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM) was performed to identify differences in apoptosis signaling between the two cell line groups. PLX4720 treatment significantly increased BIM expression in the PTEN+ (>14-fold) compared with the PTEN- cell lines (four-fold). A role for PTEN in the regulation of PLX4720-mediated BIM expression was confirmed by siRNA knockdown of PTEN and through reintroduction of PTEN into cells that were PTEN-. Further studies showed that siRNA knockdown of BIM significantly blunted the apoptotic response in PTEN+ melanoma cells. Dual treatment of PTEN- cells with PLX4720 and a PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a. In conclusion, we have shown for the first time that loss of PTEN contributes to intrinsic BRAF inhibitor resistance via the suppression of BIM-mediated apoptosis.

MeSH Terms
Apoptosis/physiology Apoptosis Regulatory Proteins/antagonists & inhibitors,biosynthesis,genetics Bcl-2-Like Protein 11 Cell Line, Tumor Drug Resistance, Neoplasm Humans Indoles/pharmacology Melanoma/drug therapy,genetics,metabolism,pathology Membrane Proteins/antagonists & inhibitors,biosynthesis,genetics Mutation PTEN Phosphohydrolase/biosynthesis,deficiency Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins/antagonists & inhibitors,biosynthesis,genetics Proto-Oncogene Proteins B-raf/antagonists & inhibitors,genetics,metabolism Proto-Oncogene Proteins c-akt/metabolism RNA, Small Interfering/administration & dosage,genetics Sulfonamides/pharmacology Up-Regulation
Chemicals
Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Indoles Membrane Proteins PLX 4720 Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors Proto-Oncogene Proteins RNA, Small Interfering Sulfonamides BRAF protein, human Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase PTEN protein, human
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Paraiso Kim H T
Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, Florida, USA.
Xiang Yun
Rebecca Vito W
Abel Ethan V
Chen Y Ann
Munko A Cecilia
Wood Elizabeth
Fedorenko Inna V
Sondak Vernon K
Anderson Alexander R A
Ribas Antoni
Palma Maurizia Dalla
Nathanson Katherine L
Koomen John M
Messina Jane L
Smalley Keiran S M
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-10-2954
Published
2011-04-01
Epub
2011-00-11
Pages
2750-60
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3070772
Subset
IM
Grants
NCI NIH HHS · P30 CA076292 · United States
NCI NIH HHS · U54 CA143970 · United States
NCI NIH HHS · U54 CA143970-01 · United States
NCI NIH HHS · P30-CA076292 · United States
Corrections
CommentIn
PMID: 21468134
CommentIn
PMID: 22121540
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-10-2954 PMC Full Text View journal details
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