SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer

• Published in: International journal of molecular sciences Vol. 22; no. 20; p. 11260
• Main Authors: Hsueh, Wei-Ting, Chen, Shang-Hung, Chien, Chia-Hung, Chou, Shao-Wen, Chi, Pei-I, Chu, Jui-Mei, Chang, Kwang-Yu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.10.2021; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antioxidants; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Colorectal cancer; Disease; Drug development; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Humans; Imidazoles - pharmacology; Kinases; Multidrug resistance; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Oxidants; Oxidizing agents; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; PI3K/mTOR pathway; Proto-Oncogene Proteins c-akt - metabolism; Quinolines - pharmacology; Rapamycin; Reactive Oxygen Species - metabolism; resistance; ROS; Signal Transduction - drug effects; SOD2; Superoxide dismutase; Superoxide Dismutase - metabolism; target therapy; Therapeutic targets; TOR protein; tumor-initiating cells; Tumors; Up-Regulation; tumor-initiating cells; PI3K/mTOR pathway; SOD2; resistance; ROS; target therapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222011260

The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant cancer cells were developed by prolonged culturing of cell lines with BEZ235, a dual PI3K and mammalian target of rapamycin (mTOR) inhibitor. The drug resistant HNC cells showed higher IC of the proliferation to inhibitors specifically targeting PI3K and/or mTOR, as compared to their parental cells. These cells also showed profound resistance to drugs of other classes. Molecular analysis revealed persistent activation of phosphorylated AKT at threonine 308 in the drug resistant cells and increased expression of markers for tumor-initiating cells. Interestingly, increased intra-cellular ROS levels were observed in the drug resistant cells. Among anti-oxidant molecules, the expression of SOD2 was increased and was associated with the ALDH-positive tumor-initiating cell features. Co-incubation of SOD inhibitors and BEZ235 decreased the stemness feature of the cells in vitro, as shown by results of the spheroid formation assay. In conclusion, dysregulation of SOD2 might contribute to the profound resistance to PI3K inhibitors and the other drugs in HNC cells.