Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC).
BACKGROUND
In order to improve therapy for HNSCC patients, novel methods to predict and combat local and/or distant tumour relapses are urgently needed. This study has been dedicated to the hypothesis that Rac1, a Rho GTPase, is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development.


METHODS
Parental and radiation-resistant (IRR) HNSCC cells were used to support this hypothesis. All cells were investigated for their sensitivity to ionising radiation and cisplatin, Rac1 activity, its intracellular expression and subcellular localisation. Additionally, tumour tissues obtained from 60 HNSCC patients showing different therapy response were evaluated for intratumoral Rac1 expression.


RESULTS
Radiation-resistant IRR cells also revealed resistance to cisplatin accompanied by increased expression, activity and trend towards nuclear translocation of Rac1 protein. Chemical inhibition of Rac1 expression and activity resulted in significant improvement of HNSCC sensitivity to ionising radiation and cisplatin. Preclinical results were confirmed in clinical samples. Although Rac1 was poorly presented in normal mucosa, tumour tissues revealed increased Rac1 expression. The most pronounced Rac1 presence was observed in HNSCC patients with poor early or late responses to chemo-radiotherapy. Tissues taken at recurrence were characterised not only by enhanced Rac1 expression but also increased nuclear Rac1 content.


CONCLUSIONS
Increased expression, activity and subcellular localisation of Rac1 could be associated with lower early response rate and higher risk of tumour recurrences in HNSCC patients and warrants further validation in larger independent studies. Inhibition of Rac1 activity can be useful in overcoming treatment resistance and could be proposed for HNSCC patients with primary or secondary chemo-radioresistance.
Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
S
S
Skvortsov
Department of Otorhinolaryngology, Innsbruck Medical University, Innsbruck, Austria.
J
J
Dudás
Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
P
P
Eichberger
Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.
M
M
Witsch-Baumgartner
Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria.
J
J
Loeffler-Ragg
Department of Otorhinolaryngology, Innsbruck Medical University, Innsbruck, Austria.
C
C
Pritz
Department of Otorhinolaryngology, Innsbruck Medical University, Innsbruck, Austria.
V H
VH
Schartinger
Section of General Pathology, Department of Pathology, Innsbruck Medical University, Innsbruck, Austria.
H
H
Maier
Translational Research Unit, European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
J
J
Hall
Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria.
P
P
Debbage
Department of Otorhinolaryngology, Innsbruck Medical University, Innsbruck, Austria.
H
H
Riechelmann
Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
P
P
Lukas
Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
I
I
Skvortsova
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D020830:rac1 GTP-Binding Protein; D002945:Cisplatin