F-actin as a functional target for retro-retinoids: a potential role in anhydroretinol-triggered cell death.
The retro-retinoids, metabolites of vitamin A (retinol), belong to a family of lipophilic signalling molecules implicated in regulation of cell growth and survival. Growth-promoting properties have been ascribed to 14-hydroxy-retro-retinol (14HRR), while anhydroretinol (AR) was discovered to act as a natural antagonist triggering growth arrest and death by apoptosis. Based on morphological studies and inhibition of apoptosis by the kinase blocker, herbimycin A, it has been suggested that retro-retinoids exhibit their function in the cytosolic compartment. F-actin emerged as a functional target for retro-retinoid action. By FACS analysis and fluorescence microscopy of phalloidin-FITC labeled cells we demonstrated that F-actin reorganization was an early event in AR-triggered apoptosis. Fluorescence images of AR-treated fibroblasts displayed short, thick, stick-like and punctate structures, and membrane ruffles at the cell periphery along with an increased diffuse staining pattern. Reversal of the AR effect by 14HRR or retinol indicates that F-actin is a common site for regulation by retro-retinoids. Inhibition of both cell death and actin depolymerisation by bcl-2 implies that cytoskeleton reorganization is downstream of bcl-2-related processes. Furthermore, stabilization of microfilaments by jasplakinolide increased the survival potential of AR treated cells, while weakening the cytoskeleton by cytochalasin B abetted apoptosis. Thus the cytoskeleton is an important way station in a communication network that decides whether a cell should live or die.
Korichneva
I
I
Program in Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. I-Korichneva@ski.mskcc.org
Hämmerling
U
U
D016475:3T3 Cells; D000199:Actins / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones; D002470:Cell Survival / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D047630:Depsipeptides; D004224:Diterpenes; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D005434:Flow Cytometry; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008223:Lymphoma; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012176:Retinoids / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000494:pharmacology
D000199:Actins; D000970:Antineoplastic Agents; D016227:Benzoquinones; D047630:Depsipeptides; D004224:Diterpenes; D047029:Lactams, Macrocyclic; D010456:Peptides, Cyclic; D011809:Quinones; D012176:Retinoids; C057531:jasplakinolide; D014801:Vitamin A; C072014:14-hydroxy-4,14-retro-retinol; D017828:Rifabutin; C031469:anhydrovitamin A; D003571:Cytochalasin B; C020754:herbimycin