Oxygenation inhibits ovarian tumor growth by downregulating STAT3 and cyclin-D1 expressions.
Hypoxia, which is commonly observed in many solid tumors, is a major impediment to chemo- or radiation therapy. Hypoxia is also known to overexpress/activate signal transducer and activator of transcription 3 (STAT3) leading to tumor progression as well as drug resistance. We hypothesized that increased oxygenation of the hypoxic tumor may have an inhibitory effect on STAT3 activation and hence tumor-growth inhibition. Mice containing human ovarian cancer xenograft tumor were exposed to hyperbaric oxygen (HBO; 100% oxygen; 2 atm; 90-min duration) daily, for up to 21 days. Mice exposed to HBO showed a significant reduction in tumor volume, with no effect on body weight. STAT3 (Tyr 705) activation and cyclin-D1 protein/mRNA levels were significantly decreased up on HBO exposure. Interestingly, HBO exposure, in combination with weekly administration of cisplatin, also significantly reduced the tumor volume; however, this group of mice had drastically reduced body weight when compared to other groups. While conventional wisdom might suggest that increased oxygenation of tumors would promote tumor growth, the results of the present study indicated otherwise. Hyperoxia appears to inhibit STAT3 activation, which is a key step in the ovarian tumor progression. The study may have important implications for the treatment of ovarian cancer in the clinic.
Selvendiran
Karuppaiyah
K
Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, USA.
Kuppusamy
M Lakshmi
ML
Ahmed
Shabnam
S
Bratasz
Anna
A
Meenakshisundaram
Guruguhan
G
Rivera
Brian K
BK
Khan
Mahmood
M
Kuppusamy
Periannan
P
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000628:therapy*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D002945:Cisplatin