Transcriptomics analysis of Nrf2 regulators in cancer resistant and long-lived naked mole-rats

Öz Objectives: Naked mole-rats (NMR, Heterocephalus glaber) have extreme resistance to cancer although they are known as the longest-living rodent with their 30-year maximum lifespan. Therefore, NMRs have rapidly emerged as a natural model for biomedical research. Studies have shown that NMRs can better tolerate stress due to mechanisms, such as upregulation of the Nrf2 pathway. Another mechanism proposed to contribute to their protection from stress involves stem cells. Therefore, in this study, we aim to identify the regulation of Nrf2 signaling in NMR fibroblasts and induced pluripotent stem cells (iPSCs). Material and Methods: The transcriptomics data of NMR and laboratory mice (Mus musculus) were used in the study. Specifically, the genes that are accepted as Nrf2 activators and inhibitors were comparatively analyzed in fibroblasts and iPSCs of both species. Results: Our data demonstrated differential expressed gene expressions between different cell lines. Among target Nrf2 activators, Palb2 RNA expression was found to be increased (p

Anahtar Kelimeler:

cancer, aging, stress resistance, Nrf2 signaling, naked mole-rat

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Lewis KT, Mele J, Hornsby PJ, Buffenstein R. Stress Resistance in the Naked Mole-Rat:The Bare Essentials – A Mini-Review. Gerontology 2012; 58: 453-462.

Lee SG, Mikhalchenko AE, Yim SH, Lobanov AV, Park JK, Choi KH, Bronson RT, Lee CK, Park TJ, Gladyshev VN. Naked mole rat induced pluripotent stem cells and their contribution to interspecific chimera. Stem Cell Rep 2017; 9: 1706-1720.

Buffenstein R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 2008; 178: 439-445.

Fang X, Wang J, Gladyshev VN et al. Adaptations to a Subterranean Environment and Longevity Revealed by the Analysis of Mole Rat Genomes. Cell Reports 2014; 8: 1354-1364.

Andziak B, O’Connor TP, Qi W, DeWaal EM, Pierce A, Chaudhuri AR, Van Remmen H, Buffenstein R. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell 2006; 5: 463-471.

Rodriguez KA, Wywial E, Perez VI, Lambert AJ, Edrey YH, Lewis KN, Grimes K, Lindsey ML, Brand MD, Buffenstein R. Walking the Oxidative Stress Tightrope: A Perspective from the Naked Mole-Rat, the Longest-Living Rodent. Curr Pharm Des 2011; 17(22): 2290-2307.

Waal EM, Liang H, Pierce A, Hamilton RT, Buffenstein R, Chaudhuri AR. Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long- living naked mole-rat: a proteomic approach. Biochemical and Biophysical Research Communications 2013; 4: 815–819.

Lewis KN, Mele J, Hayes JD, Buffenstein R. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integrative & Comparative Biology 2010; 5: 829–843.

Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 2009; 34: 176–188.

Bozaykut P, Karademir B, Yazgan B, Sozen E, Siow RC, Mann GE, Ozer NK. Effects of vitamin E on peroxisome proliferator-activated receptor γ and nuclear factorerythroid 2-related factor 2 in hypercholesterolemia induced atherosclerosis. Free Radical Biology&Medicine 2014; 70: 174–181.

Kraft AD, Johnson DA, Johnson JA. Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert –butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 2004; 24: 1101–1112.

Lemey C, Milhavet O, Lemaitre JM. iPSCs as a major opportunity to understand and cure age-related diseases. Biogerontology 2015; 16: 399-410.

Lee SG, Mikhalchenko AE, Yim SH, Gladyshev VN. A naked mole rat iPSC line expressing drug-inducible mouse pluripotency factors developed from embryonic fibroblasts. Stem Cell Reports, 2018; 197-200.

Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS ,Ueno I, Sakamoto A, Tong KI, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol 2010; 12, 213–223.

Camp ND, James RG, Dawson DW, Yan F, Davison JM, Houck SA, Tang X, Zheng N, Major MB, Moon RT. Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J Biol Chem 2012; 24;287(9):6539-50.

Mitra A, Ray A, Datta R, Sengupta S, Sarkar S. "Cardioprotective role of P38 MAPK during myocardial infarction via parallel activation of α-crystallin B and Nrf2". Journal of Cellular Physiology, 2014; 229 (9): 1272–82.

Tonelli C, Chio IIC, Tuveson DA. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal 2018;29:1727–1745.

Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends in biochemical sciences 2014; 39 (4): 99-218.

Harper JM, Salmon AB, Leiser SF, Galecki AT, Miller RA.) Skin-derived fibroblasts from long- lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone. Aging Cell 2007; 6: 1–13.

Salmon AB, Akha AAS, Buffenstein R, Miller RA. Fibroblasts from naked mole-rats are resistant to multiple forms of cell injury, but sensitive to peroxide, ultraviolet light, and endoplasmic reticulum stress. J Gerontol A Biol Sci Med Sci 2008; 63: 232-241.

Lewis KN, Wason E, Edrey YH, Kristen DM, Nevo E, Buffenstein R. Regulation of Nrf2 signaling and longevity in naturally longed-lived rodents. Proc Natl Acad Sci U S A 2015; (12): 3722–3727.

Rodriguez KA, Edrey YH, Osmulski P, Gaczynska M, Buffenstein R. Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat. PLoS ONE 2012; 7(5):e3589.

Rahman N, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet 2007; 39: 165– 167.

Ma J, Cai H, Wu T, Sobhian B, Huo Y, Alcivar A, Mehta M, Cheung K, Ganesan S, Kong AN, et al.PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol. Cell. Biol 2012; 32:1506–1517.