bims-lycede 2025-04-20 papers

Nat Commun. 2025 Apr 15. 16(1): 3554

Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization.

Yuma Saimoto, Daiki Kusakabe, Kazushi Morimoto, Yuta Matsuoka, Eisho Kozakura, Nao Kato, Kayoko Tsunematsu, Tomohiro Umeno, Tamiko Kiyotani, Shota Matsumoto, Mieko Tsuji, Tasuku Hirayama, Hideko Nagasawa, Koji Uchida, Satoru Karasawa, Mirinthorn Jutanom, Ken-Ichi Yamada.

Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.

DOI: https://doi.org/10.1038/s41467-025-58909-w

Traffic. 2025 Apr;26(4-6): e70004

Golgi Localized Arl15 Regulates Cargo Transport and Cell Adhesion.

Prerna Sharma, Pooja Hoovina Venkatesh, Shalini Samal, Neha Paddillaya, Nikita Shah, B R Rajeshwari, Abhay Bhat, Deepak Kumar Nayak, Archishman Dakua, Aravind Penmatsa, Deepak Kumar Nair, Nagaraj Balasubramanian, Namrata Gundiah, Subba Rao Gangi Setty.

Arf-like GTPases (Arls) regulate membrane trafficking and cytoskeletal organization. Genetic studies predicted a role for Arl15 in type-2 diabetes, insulin resistance, adiposity, and rheumatoid arthritis. Cell biological studies implicated Arl15 in regulating various cellular processes, including magnesium homeostasis and TGFβ signaling. However, the role of Arl15 in vesicular transport is poorly defined. We evaluated the function of Arl15 using techniques to quantify cargo trafficking to mechanobiology. Fluorescence microscopy of stably expressing Arl15-GFP HeLa cells showed its localization primarily to the Golgi and cell surface. The depletion of Arl15 causes the mislocalization of selective Golgi cargo, such as caveolin-2 and STX6, in the cells. Consistently, expression of GTPase-independent dominant negative mutants of Arl15 (Arl15V80A,A86L,E122K and Arl15C22Y,C23Y) results in mislocalization of caveolin-2 and STX6 from the Golgi. However, the localization of Arl15 to the Golgi is dependent on its palmitoylation and Arf1-dependent Golgi integrity. At the cellular level, Arl15 depleted cells display enhanced cell spreading and adhesion strength. Traction force microscopy experiments revealed that Arl15 depleted cells exert higher tractions and generate multiple focal adhesion points during the initial phase of cell adhesion compared to control cells. Collectively, these studies implicate a functional role for Arl15 in regulating cargo transport from the Golgi to regulate cell surface processes.

Keywords: Arf1; Arl15; STX6 and cell tractions; caveolin‐2

DOI: https://doi.org/10.1111/tra.70004

Semin Cancer Biol. 2025 Apr 12. pii: S1044-579X(25)00056-2. [Epub ahead of print]

Impact of tumor metabolism on tumor progression and therapy Cathepsins: emerging targets in the tumor ecosystem to overcome cancers.

Yuki Fujii, Zahra Asadi, Kamiya Mehla.

Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients' bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins' interactions, offering insights into innovative treatment strategies.

Keywords: cathepsins; chemoresistance; extracellular matrix; immune suppression; tumor microenvironment

DOI: https://doi.org/10.1016/j.semcancer.2025.04.001