EXPRESSION OF APOPTOSIS REGULATORS IN CUTANEOUS MALIGNANT-MELANOMA

Metastatic malignant melanoma (MM) is usually incurable and responds p oorly to chemotherapy. Because many cytotoxic drugs cause cell death b y inducing apoptosis, an imbalance of apoptosis regulatory proteins ma y contribute to MM treatment resistance. We have previously shown redu ced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi, It is hypothesized that other apopto sis regulators may be involved in survival of MM cells. We examined th e expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, pri mary MM, and metastatic MM using immunohistochemistry. Results were co nfirmed with Western blotting. The proapoptotic protein, Bax, was surp risingly overexpressed in all MM samples compared with benign nevi, In terestingly, in most MM samples there was overexpression of Mcl-1 or B cl-X-L, both negative regulators of apoptosis, Increased expression of Mcl-1 and Bcl-X-L was first observed in thin primary melanomas, sugge sting that up-regulation of these proteins represents a relatively ear ly event associated with malignant transformation in MM, As published previously, the majority of primary and metastatic MM exhibited reduce d Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-X-L or M cl-1, alone or in combination, may circumvent the normal cell death pa thway, contributing to the pathogenesis and treatment resistance in me tastatic MM.