Radiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT.
OBJECTIVE
Human papilloma virus (HPV)-associated cancers of the head and neck (H&N) are increasing in frequency and are often treated with radiation. There are conflicting data in the literature regarding the radiation response in the presence of HPV infection, with some data suggesting they may be more sensitive to radiation. There are few studies looking at in vitro effects of HPV and further sensitization by inhibitors of specific signaling pathways. We are in the process of starting a clinical trial in H&N cancer patients using nelfinavir (NFV) (which inhibits Akt) and it would be important to know the effect of HPV on radiation response +/- NFV.


METHODS
Two naturally infected HPV-16 cell lines (UPCI-SCC90 and UMSCC47) and the HPV-negative SQ20B H&N squamous carcinoma cells were used. Western blots with or without 10 uM NFV were done to evaluate signaling from the PI3K-Akt pathway. Clonogenic assays were done in the three cell lines with or without NFV.


RESULTS
Both UPCI-SCC90 and UMSCC47 cells were sensitive to radiation as compared with SQ20B and the degree corresponded to Akt activation. The SQ20B cell line has an activating mutation in EGFR resulting in phosphorylation (P) of Akt; UMSCC47 has decreased P-phosphatase and TENsin (PTEN), resulting in increased P-Akt; UPCI-SCC90 had overexpression of P-PTEN and decreased P-Akt. NFV resulted in downregulation of Akt in all three cell lines, resulting in sensitization to radiation.


CONCLUSIONS
HPV-infected H&N cancers are sensitive to radiation. The degree of sensitivity correlates to Akt activation and they can be further sensitized by NFV.
Gupta
Anjali K
AK
Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. anjali-gupta@uiowa.edu
Lee
John H
JH
Wilke
Werner W
WW
Quon
Harry
H
Smith
Gareth
G
Maity
Amit
A
Buatti
John M
JM
Spitz
Douglas R
DR
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000821:virology*; D052162:Human papillomavirus 16; D006801:Humans; D019888:Nelfinavir / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D030361:Papillomavirus Infections / Q000532:radiotherapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects
D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D019888:Nelfinavir