Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma.
cis-Diaminodichloroplatinum (II) (cisplatin) is one of the most effective anticancer drugs and is widely used for the treatment of squamous cell carcinoma (SCC). However, its efficacy is often limited due to the development of resistance. Although several factors implicated in cisplatin resistance have been identified, the resistance mechanisms in detail are not fully understood yet. In the present study, we have examined the implication of survival signaling pathways in cisplatin-resistance. Cisplatin induced activation of Ras and its downstream effector kinases, Raf/MEK/ERK in UM-SCC-23 human squamous cell carcinoma, suggesting that this anticancer drug activates survival signal pathway in addition to apoptosis signals. In cisplatin-resistant UM-SCC-23 in culture, which we have established, the protein levels of Ras, Raf-1 and MEK were drastically elevated compared to parent UM-SCC-23, and ERK and Akt signals were constitutively activated. U0126, an inhibitor for MEK and LY294002, an inhibitor for phosphatidylinositol 3-kinase (PI3K), sensitized resistant UM-SCC-23 to cisplatin-induced cell death. These results indicate that Raf/MEK/ERK and PI3K/Akt signal cascades may play a considerable role in cisplatin resistance in SCC.
Aoki
Kenta
K
Department of Otolaryngology, Gifu University School of Medicine, Tsukasamachi 40, Gifu 500-8705, Japan.
Ogawa
Tetsuya
T
Ito
Yatsuji
Y
Nakashima
Shigeru
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras; D006258:Head and Neck Neoplasms; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000970:Antineoplastic Agents; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin