Involvement of High Mobility Group B Proteins in Cisplatin-Induced Cytotoxicity in Squamous Cell Carcinoma of Skin

Abstract

Cis-diamminedichloroplatinum (II) (cisplatin) is a well-known anticancer drug with high potency and efficacy against various types of human cancers. Although it is widely accepted that the mechanism of cisplatin action is via apoptosis, there is enough evidence to support that cisplatin-induced cell death also occurs by other nonapoptotic pathways. Nonhistone, high mobility group (HMG) proteins are known to bind cisplatin-damaged DNA, and we studied their expression during cisplatin-induced cell death using immunohistochemistry, Western blot, and RT-PCR. Results show that the cell death is primarily apoptotic during initial stages of cisplatin treatment of skin tumors, and there is only marginal increase in high mobility group B (HMGB) levels, indicating that HMGB are still bound to nucleus. However, extended treatment of skin tumors with cisplatin caused necrosis and showed significantly increased levels of HMGB, which suggests that HMGB thus released from nuclei act as cytokine and trigger inflammatory response leading to necrosis. Present results clearly indicate a strong association between HMGB proteins and cisplatin-induced cell death that is dominantly apoptotic or necrotic depending on the duration of cisplatin exposure. Because of their important implication in the outcome of cancer chemotherapy, HMGB proteins can be interesting therapeutic targets.