bims-lycede 2025-01-05 papers

Breast Cancer Res. 2024 Dec 30. 26(1): 190

G-cleave LC3B biosensor: monitoring autophagy and assessing resveratrol's synergistic impact on doxorubicin-induced apoptosis in breast cancer cells.

Chiao-Chun Liao, Yuqing Long, Ming-Lin Tsai, Chun-Yu Lin, Kai-Wen Hsu, Chia-Hwa Lee.

Autophagy, a crucial process in cancer, is closely intertwined with both tumor progression and drug resistance development. However, existing methods used to assess autophagy activity often pose invasiveness and time-related constraints, limiting their applicability in preclinical drug investigations. In this study, we developed a non-invasive autophagy detection system (NIADS-autophagy, also called G-cleave LC3B biosensor) by integrating a split-luciferase-based biosensor with an LC3B cleavage sequence, which swiftly identified classic autophagic triggers, such as Earle's Balanced Salt Solution and serum deprivation, through protease-mediated degradation pathways. The specificity of G-cleave LC3B biosensor was confirmed via CRISPR gene editing of pivotal autophagy regulator ATG4B, yielding diminished luciferase activity in MDA-MB-231 breast cancer cells. Notably, the G-cleave LC3B biosensor exhibited strong concordance with established autophagy metrics, encompassing LC3B lipidation, SQSTM1 degradation, and puncta accumulation analysis. To underscore the usage potential of the G-cleave LC3B biosensor, we discovered that resveratrol acts as a synergistic enhancer by significantly potentiating apoptosis in MDA-MB-231 cells when combined with doxorubicin treatment. Overall, the luminescence-based G-cleave LC3B biosensor presents a rapid and dependable avenue for determining autophagy activity, thereby facilitating high-throughput assessment of promising autophagy-associated anti-cancer therapies across diverse malignancies.

Keywords: Autophagy; Breast cancer; Doxorubicin; G-cleave LC3B biosensor; Non-invasive autophagy detection system (NIADS); Resveratrol

DOI: https://doi.org/10.1186/s13058-024-01951-1

Biomark Res. 2024 Dec 31. 12(1): 165

The multifaceted roles of cathepsins in immune and inflammatory responses: implications for cancer therapy, autoimmune diseases, and infectious diseases.

Kexin Zhao, Yangqing Sun, Shangwei Zhong, Jun-Li Luo.

The cathepsin family comprises lysosomal proteases that play essential roles in various physiological processes, including protein degradation, antigen presentation, apoptosis, and tissue remodeling. Dysregulation of cathepsin activity has been linked to a variety of pathological conditions, such as cancer, autoimmune diseases, and neurodegenerative disorders. Understanding the functions of cathepsins is crucial for gaining insights into their roles in both health and disease, as well as for developing targeted therapeutic approaches. Emerging research underscores the significant involvement of cathepsins in immune cells, particularly T cells, macrophages, dendritic cells, and neutrophils, as well as their contribution to immune-related diseases. In this review, we systematically examine the impact of cathepsins on the immune system and their mechanistic roles in cancer, infectious diseases, autoimmune and neurodegenerative disorders, with the goal of identifying novel therapeutic strategies for these conditions.

Keywords: Autoimmune diseases; Cancer therapy; Cathepsins in immune cells; Infectious diseases

DOI: https://doi.org/10.1186/s40364-024-00711-9

Sci Rep. 2025 Jan 02. 15(1): 325

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.

Raffaele Pastore, Lihang Yao, Nathan Hatcher, Martin Helley, Janet Brownlees, Radha Desai.

Dysfunction of the endo-lysosomal intracellular Cholesterol transporter 2 protein (NPC2) leads to the onset of Niemann-Pick Disease Type C (NPC), a lysosomal storage disorder. Metabolic and homeostatic mechanisms are disrupted in lysosomal storage disorders (LSDs) hence we characterized a cellular model of NPC2 knock out, to assess alterations in organellar function and inter-organellar crosstalk between mitochondria and lysosomes. We performed characterization of lipid alterations and confirmed altered lysosomal morphology, but no overt changes in oxidative stress markers. Using several techniques, we demonstrated that contacts between mitochondria and late endosomes/lysosomes are reduced in NPC2-/- HEK cells, we observed that the acidic compartments are swollen and lipid dense. Quantification of endogenous lipids in HEKNPC2-/- cells by mass spectrometry reveals accumulation of lipid species indicative of sphingolipid metabolic dysregulation within the lysosome. Specifically, HEK NPC2-/- cells exhibit marked elevation of glucosylsphingosine and glucosylceramides, substrates of beta glucocerebroside (GBA), as well as accumulation of sphingosine and sphingomyelins. Our studies suggest an involvement of NPC2 in the formation of contact sites between mitochondria and lysosomes and support the hypothesis of a role for NPC2 in the endo-lysosomal trafficking pathway and dynamic organellar crosstalk.

DOI: https://doi.org/10.1038/s41598-024-83460-x