1. ¹Department of Dermatology, UCDHSC at Anschutz, Aurora, Colorado, USA
2. ²Institute for Critical Technologies and Applied Science, Virginia Tech, Blacksburg, Virginia, USA
3. ³Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA
4. ⁴Dermatology Section, Department of Veterans Affairs Medical Center, Denver, Colorado, USA

Correspondence: Dr Yiqun G. Shellman, Department of Dermatology, UCDHSC at Anschutz Medical Campus, Mail Stop #8127, PO Box 6511, Aurora, Colorado 80045, USA. E-mail: Yiqun.Shellman@uchsc.edu

Received 30 April 2007; Revised 5 July 2007; Accepted 22 August 2007; Published online 8 November 2007.

Abstract

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.