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Vitamin D Modulation of Mitochondrial Oxidative Metabolism and Mtor

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Vitamin D Modulation of Mitochondrial Oxidative Metabolism and Mtor bioRxiv preprint doi: https://doi.org/10.1101/2021.06.08.447559; this version posted June 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: Vitamin D modulation of mitochondrial oxidative metabolism and mTOR enforces 2 stress tolerance and anti-cancer responses 3 4 Authors: Mikayla Quigley1,6, Sandra Rieger1,7, Enrico Capobianco2, Zheng Wang3, 5 Hengguang Zhao4, Martin Hewison5, Thomas S. Lisse1,7* 6 7 Affiliations: 1University of Miami, Biology Department 8 1301 Memorial Drive, Cox Science Center, Coral Gables, Florida 33146 USA. 9 2Institute for Data Science and Computing, Coral Gables, Florida 33146 USA. 10 3Department of Computer Science, Coral Gables, Florida 33146 USA. 11 4Department of Dermatology, The First Affiliated Hospital of Chongqing Medical 12 University, Chongqing 400016, China. 13 5Institute of Metabolism and Systems Research, University of Birmingham, 14 Birmingham, B15 2TT, United Kingdom. 15 6Dana Farber Cancer Institute, Boston, MA 02215 USA. 16 7Sylvester Comprehensive Cancer Center, Miller School of Medicine, University 17 of Miami, Miami, Florida 33136 USA. 18 19 *Correspondence: 20 21 Thomas Lisse Ph.D. 22 Department of Biology, The University of Miami 23 [email protected] 24 305-284-3957 25 26 Keywords: Osteosarcoma, cancer, tumor, vitamin D, vitamin D deficiency, vitamin D 27 receptor, metabolism, VDR, ROS, mitochondria, MG-63, SOD, SOD1, SOD2, 28 stress, bone, osteoblast, CYP24A1, DDIT4, REDD1 29 30 Competing interests: Authors have nothing to declare. 31 32 Funding: Supported by start-up funds from the College of Arts and Sciences, Biology 33 Department, University of Miami, Coral Gables, Florida 34 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.08.447559; this version posted June 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Supported by Grant # IRG-17-183-16 from the American Cancer Society (TSL), 2 and from the Sylvester Comprehensive Cancer Center at the Miller School of 3 Medicine, University of Miami 4 5 6 Abstract 7 8 The relationship between vitamin D and reactive oxygen species (ROS), two integral signaling 9 and damaging molecules of the cell, is poorly understood. This is striking, given that both factors 10 are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of 11 the main drivers of cancer, producing higher cellular energy and ROS that can enhance 12 oxidative stress and stress tolerance responses. To study the effects of vitamin D on metabolic 13 and mt dysfunction, we used the vitamin D receptor (VDR)-sensitive MG-63 osteosarcoma cell 14 model. Using biochemical approaches, active vitamin D (1,25-dihydroxyvitamin D, 1,25(OH)2D3) 15 decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while 16 enforcing endoplasmic reticulum/mitohormetic stress tolerance responses. Using a 17 mitochondria-focused transcriptomic approach, gene set enrichment and pathway analyses 18 show that 1,25(OH)2D3 lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By 19 contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 20 1,25(OH)2D3 treatment, as well as key metabolic enzymes that regulate fluxes of substrates for 21 cellular architecture and a shift toward non-oxidative energy metabolism. ATACseq revealed 22 putative oxi-sensitive and tumor-suppressing transcription factors that may regulate important 23 mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was 24 predominantly localized to the outer mt membrane in untreated MG-63 cells yet sequestered in 25 the cytoplasm after 1,25(OH)2D3 and rotenone treatments, suggesting a level of control by 26 membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results 27 show that vitamin D activates distinct adaptive metabolic responses involving mitochondria to 28 regain redox balance and control the growth of cancer cells. 29 30 31 32 33 34 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.08.447559; this version posted June 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Introduction 2 3 The altered metabolism of cancer cells imparts a large impact on redox (reduction-oxidation) 4 homeostasis resulting in enhanced production of reactive oxygen species (ROS) that drives and 5 sustains cancer cell proliferation and evasion1. One counter measurement to elevated ROS is 6 the increase of antioxidants that allows cancer cells to persist in a damaging environment. 7 However, as cancer cells persist in the continuing pro-oxidant environment, DNA is further 8 damaged and the genome becomes more unstable with concomitant metabolic 9 reprogramming1. Over time, the metabolic reprogramming further distances cancer cells from 10 redox homeostasis, leading to a vicious cycle of accumulating genetic lesions toward cancer 11 progression. Understanding the mechanisms and how to control the dysfunctional and 12 dysregulated metabolism of cancer cells is a major challenge in cancer biology. 13 14 Perturbation of the vitamin D metabolic and signaling systems in humans and animals are 15 associated with several diseases and disorders including alopeicia2,3, osteosarcopenia4, 16 diabetes5, and cancer6. Vitamin D cellular activities are regulated primarily by the hydroxylated 17 metabolite 1-alpha, 25-dihydroxyvitamin D3 (also called 1,25(OH)2D3 or calcitriol). 1,25(OH)2D3 18 effects are mediated by the vitamin D receptor (VDR), a member of the intracellular nuclear 19 receptor superfamily7,8. A large body of studies has all implicated a suppressive role of vitamin 20 D in cancer development and improved cancer patient and animal survival6,9-12. For example, 21 elevated serum vitamin D levels at diagnosis have been linked to extended survival rates in 22 cancer patients13. And most recently, a large clinical trial involving vitamin D supplementation 23 suggests that vitamin D can benefit patients with advanced or lethal cancers by prolonging 24 mortality and survival in the study population10,14. Despite these encouraging results from the 25 clinical trial, the precise mechanism for anti-cancer effects of vitamin D remains elusive. 26 27 Understanding how what we eat (e.g., fruits and vegetables, which are rich in antioxidants like 28 vitamin C15), what we expose ourselves to (e.g., sunlight, pollution), and the metabolism that 29 can lead to energy-reducing equivalents that drive cellular replication and differentiation at the 30 genetic level provides insight toward the circle of life. In contrast, understanding how molecular 31 factors such as ROS and their antioxidants can regulate the cell cycle, differentiation, and 32 adaptive responses (e.g., DNA damage, mutagenesis) at the genetic level provides insight 33 toward the circle of death. Numerous mechanisms exist to help dictate the consequences of 34 cellular oxidative stress. For example, the cytoprotective upregulation of DNA repair transcripts 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.08.447559; this version posted June 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 allow for DNA mismatch repair, non-homologous end-joining, and base excision repair in cells to 2 handle the high levels of oxidative damage. Other avenues may consist of oxidation of 3 membrane receptors, signaling molecules, redox-sensitive transcription factors, and epigenetic 4 transcriptional regulators including histone deacetylase family members to regulate the cell’s 5 response to stress and cancer development16. Understanding the metabolic oxidation/reduction 6 reactions and cellular responses to various biological and environmental factors remains a 7 major milestone in cancer biology and therapy. 8 9 Thus, in the present study, we postulated that effects on the metabolic oxidation/reduction 10 reactions that are characteristic of cancer cells may be crucial to the anti-cancer effects of the 11 environmental/nutritional factor vitamin D. We applied genome-wide transcriptomic and 12 epigenomic approaches to provide a comprehensive understanding of how vitamin D modulates 13 mitochondrial functions and counteracts tumorigenicity within the MG-63 osteosarcoma cell 14 model, followed by mitochondrial biochemical and ultrastructural investigations. Based on these 15 approaches, we provide evidence of novel regulators of mitochondrial stress, biogenesis, 16 translation, organellar hormesis, and cancer metabolic fates mediated by vitamin D, and 17 cooperating factors leading to an overall reduction in oxidative stress levels. In particular, 18 although the tumor suppressor DNA damage inducible transcript 4 (DDIT4) is induced under 19 stress conditions in normal bone cells to inhibit metabolism activated by the mammalian target 20 of rapamycin
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