Int J Biol Sci 2021; 17(5):1203-1216. doi:10.7150/ijbs.51184 This issue Cite
1. Department of Radiation Oncology and Northwestern University, Chicago, IL, USA.
2. Driskill Graduate Program in Life Sciences, Northwestern University, Chicago, IL, USA.
3. Department of Pharmacology, Northwestern University.
4. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign.
5. Department of Pharmacology, Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
6. Department of Radiation Oncology, Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, TX, USA.
Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key post-translational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSOD-K68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSODK68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSODK68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn2+ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSOD-K68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.
Keywords: Sirtuins, SIRT3, MnSOD, SOD2, acetylation, acetylome, lysine 68, mitochondria, metabolism, carcinogenesis, aging, signaling