Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis.
OBJECTIVE
Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx.


METHODS
Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated.


RESULTS
HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs.


CONCLUSIONS
The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair.
Department of Radiotherapy and Radiooncology, BMFZ-Biomedical Research Center, Philipps-University, Hans-Meerwein-Straße 2, 35043, Marburg, Germany, arenz@med.uni-marburg.de.
Andrea
A
Arenz
Frank
F
Ziemann
Christina
C
Mayer
Andrea
A
Wittig
Kirstin
K
Dreffke
Stefanie
S
Preising
Steffen
S
Wagner
Jens-Peter
JP
Klussmann
Rita
R
Engenhart-Cabillic
Claus
C
Wittekindt
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000532:radiotherapy*; D002453:Cell Cycle / Q000528:radiation effects*; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D053938:DNA Fragmentation / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D006657:Histones / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010039:Otorhinolaryngologic Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D030361:Papillomavirus Infections / Q000473:pathology* / Q000532:radiotherapy*; D014407:Tumor Cells, Cultured / Q000473:pathology / Q000528:radiation effects*
C468783:H2AX protein, human; D006657:Histones