bims-lycede 2025-05-04 papers

JACS Au. 2025 Apr 28. 5(4): 2004-2014

Cancer Cell Identification via Lysosomal Membrane Microviscosities Using a Green-Emitting BODIPY Molecular Rotor.

Ru Ta Bagdonaitė, Rokas Žvirblis, Jelena Dodonova-Vaitku Nienė, Artu Ras Polita.

Lysosomes are dynamic, membrane-bound organelles that play key roles in cellular waste disposal, macromolecule recycling, and signaling. Disruptions in lysosomal function and lipid composition are implicated in a wide range of diseases including lysosomal storage disorders, fatty liver disease, atherosclerosis, and cancer. Imaging of the lysosomal lipid composition has the potential to not only enhance the understanding of lysosome-related diseases and their progression but also help identify them. In this work, we present a novel viscosity-sensitive, green-emitting BODIPY probe that can distinguish between ordered and disordered lipid phases and selectively internalize into the lysosomal membranes of live cells. Through the use of fluorescence lifetime imaging microscopy, we demonstrate that lysosomal membranes in multiple cancer cells exhibit significantly higher microviscosities compared to noncancer cells. The differences in lysosomal microviscosities provide an effective approach for identifying cancer cells and indicate that malignant cells may possess more oxidized and saturated lysosomal lipid membranes. Furthermore, we demonstrate the utility of viscosity-sensitive probes in quantifying the compositional changes in lysosomal membranes by investigating the effects of lysosome-permeabilizing cationic amphiphilic drugs (CADs), sertraline, and astemizole. Our results reveal that despite their functional similarities, these CADs exert opposite effects on lysosomal microviscosities in both cancerous and noncancerous cells, suggesting that different mechanisms may contribute to the CAD-induced lysosomal damage and leakage.

DOI: https://doi.org/10.1021/jacsau.5c00253

Aging Cell. 2025 May 01. e70083

TFEB Orchestrates Stress Recovery and Paves the Way for Senescence Induction in Human Dermal Fibroblasts.

Lena Guerrero-Navarro, Pablo Monfort-Lanzas, Vinzenz Krichbaumer, Mariana E G De Araújo, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, Pidder Jansen-Dürr, Maria Cavinato.

Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells show an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, leads to elevated reactive oxygen species (ROS) and lysosomal damage. ROS accumulation activates AMP-activated protein kinase (AMPK) and inhibits Akt, which correlates with the suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase aligns with the activation of transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis. TFEB knockdown under stress increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells transition to senescence, TFEB activity, required for the autophagic damage repair, becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, accompanied by the reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, is observed alongside the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results suggest a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in ensuring cellular survival during SIPS induction but becoming dispensable once senescence is established.

Keywords: SIPS; TFEB; mTOR; senescence; tBHP

DOI: https://doi.org/10.1111/acel.70083

Cell Signal. 2025 Apr 23. pii: S0898-6568(25)00247-5. [Epub ahead of print]132 111834

LAPTM5 confers cisplatin resistance in NSCLC by suppressing LAMP1 ubiquitination to stabilize lysosomal membranes and sustain autophagic flux.

Fan Wu, Chunlan Li, Xianrang Song, Li Xie.

Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.

Keywords: Autophagy; Cisplatin; LAMP1; LAPTM5; Lysosomal membrane permeabilization; ROS

DOI: https://doi.org/10.1016/j.cellsig.2025.111834