Primary tissue-based proteomic analysis of apoptosis-regulating pathways in malignant pleural mesothelioma (MPM)

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive and fatal malignancy associated with resistance to chemotherapy and radiotherapy. Programmed cell death or apoptosis underlies the efficacy of cytotoxic anti-cancer modalities, and failure to engage the cellular death machinery in cancer cells accounts for failure of therapy and poor prognosis. Little is understood of the basic apoptosis biology underlying the apoptosis resistant phenotypes of MPM. There is now greater understanding of the basic core apoptosis machinery of the cell, allowing the characterization of anti-apoptosis mechanisms in MPM. Cancer cell apoptosis threshold is ultimately determined by the location and function of proteins. This study explores the expression and significance of several proteins directly or indirectly involved in the apoptosis pathway. Histology samples were used to produce a tissue microarray (TMA) on which immunohistochemistry was employed. Proteins HIF-1α, CD31, Glut-1, CASP3, Survivin, BAX, BAK, Cyt-C, APAF-1 and PARP were analyzed and their protein expression profiles were correlated with patient survival. The findings show that MPM exhibits hypoxia. Increased glucose intake was also demonstrated by overexression of Glut-1. BAX and BAK were shown to be synergistically downregulated, with a direct effect into survival, demonstrating the compromised function of the mitochondria due to increased glucose uptake. Information yielded from this project might allow further exploitation of apoptotic proteins either as targets for new therapeutic agents, or as markers for prognosis.