Biology subjects

Lisse, T. S.

Publications and source records attributed to Lisse, T. S..

6 recordsLinked to original sources

bioRxiv2023

Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity

Taxanes are chemotherapeutic agents that induce microtubule modifications in cancer cells, resulting in cell cycle modifications and tumor remission. Here we show that paclitaxel, a widely used taxane, also induces microtubule modifications in healthy epidermal keratinocytes leading to chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel activates the cell cycle regulator, Kinesin-5 (Eg5), which promotes microtubule detyrosination and fasciculation (dfMT). Eg5 loss protects neurons from paclitaxel neurotoxicity, whereas keratinocyte-specific overexpression promotes axon degeneration. In vivo imaging and 3D reconstructions of dfMTs and nuclei, combined with mechanotransduction studies further show that dfMTs constrict keratinocyte nuclei, leading to nuclear Nox-dependent reactive oxygen species (X-ROS) formation upstream of MMP-13 and cutaneous sensory axon degeneration. This new insight facilitates our understanding of chemotherapy side effects and highlights the need for targeted therapies.

cell biology↗

bioRxiv2023

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on the NMD-ROS-EMT signaling axis in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDRs integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.

cancer biology↗

bioRxiv2021

Vitamin D modulation of mitochondrial oxidative metabolism and mTOR enforces stress tolerance and anti-cancer responses

The relationship between vitamin D and reactive oxygen species (ROS), two integral signaling and damaging molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing higher cellular energy and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of vitamin D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)-sensitive MG-63 osteosarcoma cell model. Using biochemical approaches, active vitamin D (1,25-dihydroxyvitamin D, 1,25(OH)2D3) decreased mt ROS levels, membrane potential ({Delta}{Psi}mt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress tolerance responses. Using a mitochondria-focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D3 lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D3 treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non-oxidative energy metabolism. ATACseq revealed putative oxi-sensitive and tumor-suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG-63 cells yet sequestered in the cytoplasm after 1,25(OH)2D3 and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that vitamin D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of cancer cells.

cancer biology↗

bioRxiv2020

Vitamin D regulation of a SOD1-to-SOD2 antioxidative switch to prevent osteosarcoma transformation

Superoxide, a form of reactive oxygen species (ROS), is catabolized by superoxide dismutase (SOD) and contributes to carcinogenesis via the oxidative damage it inflicts on cells. The aim of this research was to analyze the potential vitamin D-mediated regulation of the antioxidative "SOD1-to-SOD2 switch" within the human MG-63 osteosarcoma model. For this study, real-time PCR analysis was performed using MG-63 cells exposed to metabolically active 1,25(OH)2D3. Frist, a sustained statistically significant >2-fold suppression of proliferating cell nuclear antigen (PCNA) transcripts was observed after 10nM but not at 100nM of 1,25(OH)2D3 treatment, suggesting a cytostatic effect. In order to assess regulators of mitochondrial oxidative phosphorylation, gene expression of COX2 and COX4l1 of the mitochondrial complex IV and antioxidative enzymes (SOD1, SOD2 and Catalase (CAT)) were monitored. For COX2 and COX4l1, no changes in gene expression were observed. However, a concomitant decrease in CAT and SOD1 mRNA, and increase in SOD2 mRNA after 24 hours of 10nM 1,25(OH)2D3 treatment were observed. A ~8-fold increase in SOD2 mRNA was apparent after 48 hours. The significant increase in SOD2 activity in the presence of vitamin D indicates an antioxidant potential and sensitization of vitamin D during osteosarcoma transformation and mitochondrial detoxification over time.

cancer biology↗

bioRxiv2020

Dicer- and BSC-dependent miRNAs during murine anagen development

MicroRNAs (miRNAs) are a major class of conserved non-coding RNAs that have a wide range of functions during development and disease. Biogenesis of canonical miRNAs depend on the cytoplasmic processing of pre-miRNAs to mature miRNAs by the Dicer endoribonuclease. Once mature miRNAs are generated, the miRNA-induced silencing complex, or miRISC, incorporates one strand of miRNAs as a template for recognizing complementary target messenger RNAs (mRNAs) to dictate post-transcriptional gene expression. Besides regulating miRNA biogenesis, Dicer is also part of miRISC to assist in activation of the complex. Dicer associates with other regulatory miRISC co-factors such as trans-activation responsive RNA-binding protein (Tarbp2) to regulate miRNA-based RNA interference. Although the functional role of miRNAs within epidermal keratinocytes have been extensively studied within embryonic and post-natal mouse skin, its contribution to the normal function of hair follicle bulge stem cells (BSCs) during post-natal hair follicle development is unknown. With this question in mind, we sought to ascertain whether Dicer-Tarpb2 plays a functional role within BSCs during induced anagen development by utilizing conditional knockout mouse models. Our findings suggest that Dicer, but not Tarbp2, functions within BSCs to regulate induced anagen (growth) development of post-natal hair follicles. These findings strengthen our understanding of miRNA-dependency within hair follicle cells to define a boundary for post-transcriptional gene regulation during anagen development.

molecular biology↗

bioRxiv2019

Short-wavelength violet light (420nm) stimulates melanopsin-dependent acute alertness responses in zebrafish

Sunlight throughout the day and seasons strongly influences our biological rhythms and activity. In recent years, it has become evident that night-time overexposure to bright light in urban environments can profoundly affect physiology and behaviour in humans and animals. In particular, the artificial emission of short-wavelength light has been shown to stimulate alertness in humans, but the mechanisms remain largely unknown. Utilising a diurnal larval zebrafish model, we identified instant, non-image-forming (NIF) responses to short-wavelength violet light (~420nm), which are activated only during light exposure, and are reminiscent of alertness, including increased heart rate, enhanced locomotor activity, and pectoral fin beating (for increased oxygen supply). We further determined that these responses are driven by sympathetic neuronal circuits and depend on the zebrafish melanopsin homologue Opn4a. We also found that these responses can be modulated by the sleep-regulatory hormone melatonin, but that melatonin is not essential. Our findings reveal a previously unknown mechanism for violet light-dependent acute alertness.

animal behavior and cognition↗