Targeting endocytosis to sensitize cancer cells to programmed cell death.

Evading programmed cell death (PCD) is a hallmark of cancer that allows tumor cells to survive and proliferate unchecked. Endocytosis, the process by which cells internalize extracellular materials, has emerged as a key regulator of cell death pathways in cancer. Many tumor types exhibit dysregulated endocytic dynamics that fuel their metabolic demands, promote resistance to cytotoxic therapies, and facilitate immune evasion. This review examines the roles of endocytosis in apoptotic resistance and immune escape mechanisms utilized by cancer cells. We highlight how inhibiting endocytosis can sensitize malignant cells to therapeutic agents and restore susceptibility to PCD. Strategies to modulate endocytosis for enhanced cancer treatment are discussed, including targeting endocytic regulatory proteins, altering membrane biophysical properties, and inhibiting Rho-associated kinases. While promising, challenges remain regarding the specificity and selectivity of endocytosis-targeting agents. Nonetheless, harnessing endocytic pathways represents an attractive approach to overcome apoptotic resistance and could yield more effective therapies by rendering cancer cells vulnerable to PCD. Understanding the interplay between endocytosis and PCD regulation is crucial for developing novel anticancer strategies that selectively induce tumor cell death.

Mechano-inhibition of endocytosis sensitizes cancer cells to Fas-induced Apoptosis.

The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.

Tension-induced adhesion mode switching: the interplay between focal adhesions and clathrin-containing adhesion complexes.

Integrin-based adhesion complexes are crucial in various cellular processes, including proliferation, differentiation, and motility. While the dynamics of canonical focal adhesion complexes (FAs) have been extensively studied, the regulation and physiological implications of the recently identified clathrin-containing adhesion complexes (CCACs) are still not well understood. In this study, we investigated the spatiotemporal mechanoregulations of FAs and CCACs in a breast cancer model. Employing single-molecule force spectroscopy coupled with live-cell fluorescence microscopy, we discovered that FAs and CCACs are mutually exclusive and inversely regulated complexes. This regulation is orchestrated through the modulation of plasma membrane tension, in combination with distinct modes of actomyosin contractility that can either synergize with or counteract this modulation. Our findings indicate that increased membrane tension promotes the association of CCACs at integrin αVß5 adhesion sites, leading to decreased cancer cell proliferation, spreading, and migration. Conversely, lower membrane tension promotes the formation of FAs, which correlates with the softer membranes observed in cancer cells, thus potentially facilitating cancer progression. Our research provides novel insights into the biomechanical regulation of CCACs and FAs, revealing their critical and contrasting roles in modulating cancer cell progression.

Dynamic interplay between cell membrane tension and clathrin-mediated endocytosis.

Deformability of the plasma membrane, the outermost surface of metazoan cells, allows cells to be dynamic, mobile and flexible. Factors that affect this deformability, such as tension on the membrane, can regulate a myriad of cellular functions, including membrane resealing, cell motility, polarisation, shape maintenance, membrane area control and endocytic vesicle trafficking. This review focuses on mechanoregulation of clathrin-mediated endocytosis (CME). We first delineate the origins of cell membrane tension and the factors that yield to its spatial and temporal fluctuations within cells. We then review the recent literature demonstrating that tension on the membrane is a fast-acting and reversible regulator of CME. Finally, we discuss tension-based regulation of endocytic clathrin coat formation during physiological processes.

Inductive modulation of tris(phosphinomethyl)phenylborate donation at group VI metals via borate phenyl substituent modification.

A series of zerovalent group VI metal complexes of tris(diisopropylphosphinomethyl)phenylborate ([PhB(CH2PiPr2)3]-, PhBPiPr3), including [PPN][M(CO)3(PhBPiPr3)] (M = Cr, Mo, W) and the first bimetallics in which PhBPiPr3 serves as a bridging ligand via binding M(CO)3 units at the three phosphorus atoms and the borate phenyl substituent, have been synthesized and fully characterized. Two new tris(phosphinomethyl)borates featuring 3,5-dimethylphenyl and 3,5-bis(trifluoromethyl)phenyl borate substituents were prepared as crystallographically characterized thallium salts, and metallated giving their inaugural transition metal complexes [PPN][M(CO)3(((3,5-Me)C6H3)BPPh3)] and [PPN][M(CO)3(((3,5-CF3)C6H3)BPPh3)]. A comparative ν(CO) infrared spectroscopic analysis and examination of half wave potentials assessed by cyclic voltammetry supports a ligand donor ranking of Tp > PhBPiPr3 ≥ Cp > PhBPPh3 > triphos. For these anionic complexes, in which a lower electrostatic contribution to zerovalent metal-PhBPR3 binding is likely operative relative to that present in the zwitterionic complexes most commonly prepared with tris(phosphinomethyl)borates, PhBPR3 ligands do not function as strongly donating scorpionates. Nevertheless, PhBPPh3 is a substantially stronger donor than triphos towards zerovalent M(CO)3; the half wave potentials of [Et4N][M(CO)3(PhBPPh3)] are ∼340 mV lower than those of M(CO)3(triphos). The potentials of the ((3,5-Me)C6H3)BPPh3 group VI metal tricarbonyl anions are more negative than those of the corresponding ((3,5-CF3)C6H3)BPPh3 group VI metal tricarbonyl anions by ∼50 mV, suggesting a modest, yet rational, tuning of PhBPPh3 donation via inductive modulation of the borate anion charge.