Mechano-inhibition of endocytosis sensitizes cancer cells to Fas-induced Apoptosis.
Mehmet H KuralUmidahan DjakbarovaBilal CakirYoshiaki TanakaEmily T ChanValeria I Arteaga MunizYasaman MadrakiHong QianJinkyu ParkLorenzo R SewananIn-Hyun ParkLaura E NiklasonComert KuralPublished in: Cell death & disease (2024)
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.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- mouse model
- diabetic rats
- cancer therapy
- poor prognosis
- cell surface
- papillary thyroid
- risk assessment
- multiple sclerosis
- squamous cell carcinoma
- binding protein
- brain injury
- cell proliferation
- drug delivery
- high glucose
- white matter
- long non coding rna
- subarachnoid hemorrhage
- cerebral ischemia
- drug induced
- childhood cancer
- smooth muscle
- protein kinase