Abstract
Background: The expression and activity of ribonucleotide reductase (RR) has been associated with resistance to multiple drugs in human cancer. The use of antisense oligonucleotide drug, GTI-2040, a 20-mer phosphorothioate oligonucleotide complemented to the human RR M2 subunit mRNA, represents an effective strategy for inhibiting RR. The increased specificity due to the anti-resistance effect of GTI-2040 may also lead to a more favorable therapeutic outcome. Materials and Methods: To understand the molecular mechanism underlying RR inhibition, patients' blood samples were analyzed using multiple dimensional proteomics technology via matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: A major difference occurred at 5k mlz in the MALDI profile, which appeared only in the non-responsive group and diminished after GTI-2040 treatment. This specific peptide peak remained at the basal level in responsive patients. The peak was identified to represent the F-box/LLR-repeat protein 17 (FBXL17) through nanoelectrospray ionization liquid chromatography-tandem mass spectrometry (nanoESI LC-MS/MS). Further characterization revealed that FBXL17/SKP2 directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7. Conclusion: Validation of this protein using real-time RT-PCR indicates the F-box protein 17 (FBXL17) can serve as a therapeutic target and surrogate marker for breast cancer therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 151-160 |
| Number of pages | 10 |
| Journal | Cancer Genomics and Proteomics |
| Volume | 5 |
| Issue number | 3-4 |
| Publication status | Published - Jan 1 2008 |
| Externally published | Yes |
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Keywords
- Biomarker
- Breast cancer
- Proteomics
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy. / Xiao, Gary Guishan; Zhou, Bing Sen; Somlo, George; Portnow, Jana; Juhasz, Agnes; Un, Frank; Chew, Helen; Gandara, David; Yen, Yun.
In: Cancer Genomics and Proteomics, Vol. 5, No. 3-4, 01.01.2008, p. 151-160.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of F-box/LLR-repeated protein 17 as potential useful biomarker for breast cancer therapy
AU - Xiao, Gary Guishan
AU - Zhou, Bing Sen
AU - Somlo, George
AU - Portnow, Jana
AU - Juhasz, Agnes
AU - Un, Frank
AU - Chew, Helen
AU - Gandara, David
AU - Yen, Yun
PY - 2008/1/1
Y1 - 2008/1/1
N2 - Background: The expression and activity of ribonucleotide reductase (RR) has been associated with resistance to multiple drugs in human cancer. The use of antisense oligonucleotide drug, GTI-2040, a 20-mer phosphorothioate oligonucleotide complemented to the human RR M2 subunit mRNA, represents an effective strategy for inhibiting RR. The increased specificity due to the anti-resistance effect of GTI-2040 may also lead to a more favorable therapeutic outcome. Materials and Methods: To understand the molecular mechanism underlying RR inhibition, patients' blood samples were analyzed using multiple dimensional proteomics technology via matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: A major difference occurred at 5k mlz in the MALDI profile, which appeared only in the non-responsive group and diminished after GTI-2040 treatment. This specific peptide peak remained at the basal level in responsive patients. The peak was identified to represent the F-box/LLR-repeat protein 17 (FBXL17) through nanoelectrospray ionization liquid chromatography-tandem mass spectrometry (nanoESI LC-MS/MS). Further characterization revealed that FBXL17/SKP2 directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7. Conclusion: Validation of this protein using real-time RT-PCR indicates the F-box protein 17 (FBXL17) can serve as a therapeutic target and surrogate marker for breast cancer therapy.
AB - Background: The expression and activity of ribonucleotide reductase (RR) has been associated with resistance to multiple drugs in human cancer. The use of antisense oligonucleotide drug, GTI-2040, a 20-mer phosphorothioate oligonucleotide complemented to the human RR M2 subunit mRNA, represents an effective strategy for inhibiting RR. The increased specificity due to the anti-resistance effect of GTI-2040 may also lead to a more favorable therapeutic outcome. Materials and Methods: To understand the molecular mechanism underlying RR inhibition, patients' blood samples were analyzed using multiple dimensional proteomics technology via matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: A major difference occurred at 5k mlz in the MALDI profile, which appeared only in the non-responsive group and diminished after GTI-2040 treatment. This specific peptide peak remained at the basal level in responsive patients. The peak was identified to represent the F-box/LLR-repeat protein 17 (FBXL17) through nanoelectrospray ionization liquid chromatography-tandem mass spectrometry (nanoESI LC-MS/MS). Further characterization revealed that FBXL17/SKP2 directly interacts with the human RR M2 (RRM2) subunit to promote hRRM2 overexpression in the breast cancer cell line MCF-7. Conclusion: Validation of this protein using real-time RT-PCR indicates the F-box protein 17 (FBXL17) can serve as a therapeutic target and surrogate marker for breast cancer therapy.
KW - Biomarker
KW - Breast cancer
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=46849103628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=46849103628&partnerID=8YFLogxK
M3 - Article
C2 - 18820369
AN - SCOPUS:46849103628
VL - 5
SP - 151
EP - 160
JO - Cancer Genomics and Proteomics
JF - Cancer Genomics and Proteomics
SN - 1109-6535
IS - 3-4
ER -