Enhanced ubiquitinylation of heat shock protein 90 as a potential mechanism for mitotic cell death in cancer cells induced with hypericin.
A unique property of the photodynamic signal transduction inhibitor hypericin is functionality in the dark. We show in tumor cells that hypericin targets the heat shock protein (Hsp) 90 chaperone but not Hsp70 (Hsc70) to enhanced ubiquitinylation. As a consequence Hsp90 chaperone functionality is abrogated and the client proteins, mutant p53, Cdk4, Raf-1, and Plk, are displaced from complexes with Hsp90, destabilized, and degraded via a proteasome-independent pathway. Decline in Raf-1 prevents downstream activation of extracellular signal-regulated kinase 1/2 kinases, the Ras/Raf pathway is inhibited, and tumor cell proliferation is arrested. The cells exhibit multiple aberrations including retardation at G(2)-M, increased cell volume, and multinucleation, all of which are hallmarks of mitotic cell death. The studies demonstrate that ubiquitinylation of Hsp90 inactivates the chaperone, destabilizes the plethora of client proteins, and creates deficiencies in multiple unrelated cellular functions. This combination constitutes a mechanism by which hypericin generates mitotic cell death in cancer cells.
Blank
Michael
M
Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Mandel
Mathilda
M
Keisari
Yona
Y
Meruelo
Daniel
D
Lavie
Gad
G
D000818:Animals; D000873:Anthracenes; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003624:Darkness; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
D000873:Anthracenes; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D025801:Ubiquitin; D010569:Perylene; C004965:hypericin