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

Abstract

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 IC50 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.

Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations

“…Head and neck (HNC) cancer cell lines resistant to the PI3K inhibitor BEZ235 showed increased ROS and ALDH expression. It is possible that the increased ROS was buffered, in part by ALDH, however there was no functional assessment of oxphos levels in this study to understand the source of the ROS ( Hsueh et al, 2021 ). Instead, the authors noted that superoxide dismutase 2 (SOD2) was increased in the resistant cells.…”

“…Further, SOD2 is in the mitochondrial matrix and is the major processor of ETC generated superoxide ( Karnati et al, 2013 ). This may suggest that ROS generated within the mitochondria of the BEZ235 resistant cells was due to oxphos activity ( Hsueh et al, 2021 ). Sirtuins (SIRTs), a family of deacetylases, may be able to buffer oxphos generated ROS in cancer ( Kim et al, 2010 ; Bell et al, 2011 ).…”

Insights into Manganese Superoxide Dismutase and Human Diseases

“…MnSOD can directly mediate multiple cancer cell death signalling pathways, including apoptosis [206], pyroptosis [207], and autophagy [208]. High MnSOD expression contributes to chemoresistance [209][210][211] and radioresistance [212,213] in different cancer types. Recently, posttranslational modification of MnSOD, with particular emphasis on acetylation at lysine residue 68, was proposed and explored, which addressed its vital roles in promoting cancer progression [214][215][216].…”