Identification of hypoxia-regulated proteins in head and neck cancer by proteomic and tissue array profiling.
Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased >/=1.5-fold during hypoxia. The majority of these proteins such as IkappaB kinase beta (IKKbeta), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150(glued), nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKbeta, a regulator of the nuclear factor-kappaB transcription factor, during hypoxia. We demonstrated that IKKbeta mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKbeta expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKbeta is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.
Chen
Yijun
Y
Department of Radiation Oncology, Center for Clinical Sciences Research, Department of Surgery, Palo Alto VA Health Care System, Palo Alto, CA, USA.
Shi
Gongyi
G
Xia
Wei
W
Kong
Christina
C
Zhao
Shuchun
S
Gaw
Allison F
AF
Chen
Eunice Y
EY
Yang
George P
GP
Giaccia
Amato J
AJ
Le
Quynh-Thu
QT
Koong
Albert C
AC
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D051356:Cortactin; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D051550:I-kappa B Kinase; D008297:Male; D008840:Microfilament Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D040901:Proteomics; D046888:Tissue Array Analysis; D015854:Up-Regulation
D051356:Cortactin; D006360:Heat-Shock Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D010100:Oxygen