Proteomics-based identification of biomarkers for predicting sensitivity to a PI3-kinase inhibitor in cancer

Akashi, Tetsuyuki; Nishimura, Yumiko; Wakatabe, Rumi; Shiwa, Mieko; Yamori, Takao

doi:10.1016/j.bbrc.2006.11.052

Cited by 13 publications

(14 citation statements)

References 25 publications

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“…All cell lines were tested to be mycoplasma free using a PCR ELISA assay (Roche Diagnostics Inc., Indianapolis). HCT116 K-Ras-deleted cells generated by homologous deletion of the mutant K-Ras allele [20, 21] were transfected by electroporation at 600 V for 60 milliseconds using a Multiporator Eppendorf (Hamburg, Germany) with G418 selectable plasmids expressing mutant active H-Ras (H-Ras V12), and the selective effectors H-Ras V12S35, H-Ras V12G37, or H-Ras V12C40, which preferentially activate Raf, RalGDS, and PI-3-kinase enzymes, respectively, and individual colonies isolated. The plasmids were generously provided by Dr. M. Wigler (Cold Spring Harbor, NY).…”

Section: Methodsmentioning

confidence: 99%

“…As PX-866 and other specific inhibitors of PI-3-kinase/Akt signaling move through clinical development, the identification of positive and negative predictors of response to identify individuals most likely to receive the maximum therapeutic benefit is critical. Predictors for PI-3-kinase/Akt inhibitor sensitivity so far reported include PI-3-kinase pathway -specific mutations (7, 10–12) increased insulin like growth factor binding protein-2 (IGFBP-2) in glioma (19), stathmin in breast cancer (20) and acidic ribosomal phosphoprotein P2 (21). …”

Section: Introductionmentioning

confidence: 99%

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Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance

et al. 2008

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The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived from cell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTEN activity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3K inhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI3K signaling measured by tumor phosphorylated Ser 473 -Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse-phase protein array revealed that the Rasdependent downstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best-defined downstream targets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through its ability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI3K inhibition might serve as an important guide for patient selection as inhibitors enter clinical trials and for the development of rational combinations with other molecularly targeted agents.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance

et al. 2008

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“…Recently, new strategies that facilitate proteomic analysis, such as, the surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) have been introduced [17]. This technology uses protein chips made of a variety of chromatographic surfaces to capture proteins from a complex mixture that are subsequently ionized and detected by TOF MS and provides a peak whose intensity is relatively quantitative and reproducible measure of a particular protein [16,18,19]. Changes in the protein peaks, or m/z ratios within the spectra, can be used to identify protein changes that may underlie in pathophysiological processes.…”

Section: Introductionmentioning

confidence: 99%

Effect of Turkish propolis extracts on proteome of prostate cancer cell line

et al. 2011

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BackgroundPropolis is a natural, resinous hive product that has several pharmacological activities. Its composition varies depending on the vegetation, climate, season and environmental conditions of the area from where it was collected. Surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) is a proteomic approach which has been used in cancer proteomics studies. Prostate cancer is one of the most commonly diagnosed cancers in men. It has shown that nutritional supplements rich in polyphenolic compounds such as propolis play a significant role in prostate cancer chemoprevention. The aim of this study is to evaluate if protein expression profile in PC-3 prostate cancer cell lines could be differentiated when incubated with dimethyl sulfoxide and water extracts of Turkish propolis.ResultsThe antioxidant potentials of dimethyl sulfoxide and water extracts of propolis were found in correlation with the amount of total phenolic compounds of them. Dimethyl sulfoxide and water extracts of propolis of 20 μg/mL reduced the cell viability to 24.5% and 17.7%, respectively. Statistically significant discriminatory peaks between control PC-3 cells and dimethyl sulfoxide extract of propolis-treated PC-3 cells were found to be the proteomic features at m/z 5143, 8703, 12661, 20184 and 32794, detected by CM10 ProteinChip, and the peak at m/z 3772, detected by Q10 ProteinChip. Between control PC-3 cells and water extract of propolis-treated PC-3 cells, statistically significant discriminatory peaks were found to be the proteomic features at m/z 15846, 16052 and 24658, detected by CM10 ProteinChip and the peaks at m/z 10348, 10899 and 11603, detected by Q10 ProteinChip.ConclusionsIt was concluded that dimethyl sulfoxide and water extracts of Turkish propolis may have anti-proliferative activity through differentiating protein expression profile in PC-3 prostate cancer cell lines along with their antioxidant capacity.

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“…These results may provide new insights into EGFR phosphorylation signaling and have implications in molecular cancer therapy of NPC. Akashi et al [27] measured the expression of 393 proteins in 39 human cancer cell lines (JFCR-39). Using an integrated approach allowed us to identify two peaks at 11.6 and 11.8 kD that showed significant correlations with sensitivity to the PI3K inhibitor, LY294002.…”

Section: Tumor and Proteomics Of Post-translational Modificationsmentioning

confidence: 99%