Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response.
Almost instantaneously after the treatment of mouse SCCVII tumor cells with Photofrin-based photodynamic therapy (PDT), a fraction (15-25%) of total cellular heat shock protein 70 (HSP70) became exposed at the cell surface. The level of this surface-expressed HSP70 then remained unchanged for the next 6 hours and persisted at lower levels even at 18 hours after PDT. A similar induction of surface HSP70 expression was found with PDT-treated human umbilical vein endothelial cells. The same analysis for several other HSPs revealed the induced surface expression of HSP60 and GRP94, but not GRP78, on PDT-treated SCCVII cells. A fraction of total HSP70 existing in SCCVII cells at the time of PDT treatment was promptly (within 1 hour) released from cells after high treatment doses, whereas even lower PDT doses induced a substantial HSP70 release at later time intervals. Macrophages coincubated with PDT-treated SCCVII cells displayed elevated levels of both HSP70 and GRP94 on their surface and were stimulated to produce tumor necrosis factor alpha, whose production was inhibited by the presence of antibodies against either HSP70, Toll-like receptors 2 and 4, or specific NF-kappaB inhibitor in the coincubation medium. The induction of cell surface expression and release of HSPs by PDT may represent an important event in the response of tumors to this treatment modality with a critical role in the induced inflammatory and immune responses that contribute to the therapeutic outcome.
Korbelik
Mladen
M
British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. mkorbeli@bccancer.bc.ca
Sun
Jinghai
J
Cecic
Ivana
I
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D018920:Coculture Techniques; D017323:Dihematoporphyrin Ether / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D010778:Photochemotherapy; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D017323:Dihematoporphyrin Ether