Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics.

Https://doi.org/10.18632/oncotarget.27649 Janos Schmidt, Béla Kajtár, Kata Juhász, Mária Péter, Tamás Járai, András Burián, László Kereskai, Imre Gerlinger, Tamás Tornóczki, Gábor Balogh, László...

GBM accounts for most of the fatal brain cancer cases, making it one of the deadliest tumor types. GBM is characterized by severe progression and poor prognosis with a short survival upon conventional chemo- and radiotherapy. In order to improve therapeutic efficiency, considerable efforts have been made to target various features of GBM. One of the targetable features of GBM is the rewired lipid metabolism that contributes to the tumor’s aggressive growth and penetration into the surrounding brain tissue. Lipid reprogramming allows GBM to acquire survival, proliferation, and invasion benefits as well as supportive modulation of the tumor microenvironment. Several attempts have been made to find novel therapeutic approaches by exploiting the lipid metabolic reprogramming in GBM. In recent studies, various components of de novo lipogenesis, fatty acid oxidation, lipid uptake, and prostaglandin synthesis have been considered promising targets in GBM. Emerging data also suggest a significant role hence therapeutic potential of the endocannabinoid metabolic pathway in GBM. Here we review the lipid-related GBM characteristics in detail and highlight specific targets with their potential therapeutic use in novel antitumor approaches.

The plasma membrane (PM) of eukaryotic cells plays a key role in the response to stress, acting as the first line of defense against environmental changes and protecting cells against intracellular perturbations. In this work, we explore how membrane-bound chaperones and membrane lipid domains work together to shape plasma membrane properties—a partnership we refer to as the “epichaperome–plasma membrane lipid axis.” This axis influences membrane fluidity, curvature, and domain organization, which in turn shapes the spatial and temporal modulation of signaling platforms and pathways essential for maintaining cellular integrity and homeostasis. Changes in PM fluidity can modulate the activity of ion channels, such as transient receptor potential (TRP) channels. These changes also affect processes such as endocytosis and mechanical signal transduction. The PM proteome undergoes rapid changes in response to membrane perturbations. Among these changes, the expression of heat shock proteins (HSPs) and their accumulation at the PM are essential mediators in regulating the physical state and functional properties of the membrane. Because of the pivotal role in stress adaptation, HSPs influence a wide range of cellular processes, which we grouped into three main categories: (i) mechanistic insights, differentiating in vitro (liposome, reconstituted membrane systems) and in vivo evidence for HSP-PM recruitment; (ii) functional outputs, spanning how ion channels are affected, changes in membrane fluidity, transcytosis, and the process of endocytosis and exosome release; and (iii) pathological effects, focusing on how rewired lipid–chaperone crosstalk in cancer drives resistance to drugs through altered membrane composition and signaling. Finally, we highlight Membrane Lipid Therapy (MLT) strategies, such as nanocarriers targeting specific PM compartments or small molecules that inhibit HSP recruitment, as promising approaches to modulate the functional stability of epichaperome assembly and membrane functionality, with profound implications for tumorigenesis.

Background: Silver nanoparticles (AgNPs) have a broad spectrum of biocidal effects, allowing also their antitumor application. To enhance bioavailability, minimize adverse effects and enable targeted drug delivery AgNPs may be encapsulated in liposomes. In this study we aimed to create highly stable and effective antitumor AgNP lipid formulations (LAgs). Methods: Uncapped and citrate-stabilized AgNPs were encapsulated by the lipid film hydration method using several phospholipid mixtures, followed by the essential removal of unencapsulated AgNPs by size exclusion chromatography (SEC). Purified LAgs were characterized by UV-VIS, DLS, XRD, ICP-MS, transmission electron microscopy (TEM) and glycerol-based density gradient centrifugation (DGC). Liposomal stability was assessed by carboxyfluorescein (CF) leakage, while antitumor effects of purified LAgs were tested in MTT, clonogenic and 3D spheroid invasion experiments. Results: The presence of AgNPs inside SEC-purified liposomes was confirmed by TEM, XRD and ICP-MS. Encapsulation efficiency was estimated to be between 18.7 and 25.5%. Purified LAgs had higher density as compared to free AgNPs revealed by DGC, indicating that a considerable fraction of liposomes contained AgNPs. LAgs with PC/PG, PC/PG/SM/Chol, and in particular PC/PG/SM displayed the highest stability assessed by CF leakage, whereas high content of neutral or negatively charged phospholipids was destabilizing. As shown by MTT and colony formation assays, viability and survival of A375 and RPMI-7951 melanoma cells were severely impaired by LAgs at a higher or comparable level as caused by free AgNPs. Used as a non-tumor control, HEK293 cells were less vulnerable to LAgs as compared to free AgNPs. Finally, applying the most stable lipid composition, PC/PG/SM-LAg-c, and in part PC/PG/SM-LAg-u effectively inhibited a tissue-like invasion of melanoma spheroids. Conclusion: Altogether, highly stable purified LAg formulations were created, which effectively block survival, clonogenic potential and invasion of melanoma cells, therefore could be promising NP platforms for targeted tumor therapy.