Hyperthermia induces endoplasmic reticulum-mediated apoptosis in melanoma and non-melanoma skin cancer cells.
Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.
Shellman
Yiqun G
YG
Department of Dermatology, UCDHSC at Anschutz, Aurora, Colorado 80045, USA. Yiqun.Shellman@uchsc.edu
Howe
William R
WR
Miller
Leslie A
LA
Goldstein
Nathaniel B
NB
Pacheco
Theresa R
TR
Mahajan
Roop L
RL
LaRue
Susan M
SM
Norris
David A
DA
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D008545:Melanoma / Q000378:metabolism / Q000628:therapy*; D018832:Molecular Chaperones / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000628:therapy*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D020169:Caspases