The serum level of
lactate dehydrogenase (LDH) is an important predictor of prognosis and treatment response in
melanoma patients. It is unknown whether the expression of LDH-5 in tissue sections also has prognostic significance and whether it is related to the expression of the
anti-apoptotic proteins, Bcl-2, Bcl-XL and Mcl-1, and endoplasmic reticulum stress
protein glucose-regulated
protein 78 (
GRP78). Identification of an association between LDH-5 expression and
anti-apoptotic proteins may have important therapeutic implications for
melanoma patients. Sections from 159 pigmented lesions, including
nevi and
melanoma at different stages of progression were studied by immunohistochemistry. Correlation of LDH-5 expression with clinicopathological factors and with the expression of Bcl-2, Bcl-XL, Mcl-1 and
GRP78 was examined. LDH-5 was detected at low levels in 6 of 10 compound
nevi (60%) and 6 of 10
dysplastic nevi (60%). The percentage of positive cases was greater in thin (<or=1.0 mm) (74%) and thick primary
melanoma (>1.0 mm) (95%) and in metastatic
melanoma in the skin (100%) and lymph node (81%). The immunoreactive score was highly related to progression of
melanoma (P<0.0001). LDH-5 expression was positively associated with increasing
tumor thickness (P=0.02) and dermal
tumor mitotic rate (P=0.02). LDH-5 above the median immunoreactive score was associated with reduced disease-free survival and overall survival (P<0.02). LDH-5 expression was negatively associated with Bcl-2 expression. In contrast, LDH-5 expression was strongly associated with Bcl-XL and Mcl-1 expression and also positively associated with
GRP78 expression (P<0.0001). The low Bcl-2 expression in
melanomas with high LDH-5 expression provides an explanation for the poor response of patients with high serum LDH levels to treatment with the Bcl-2 antisense drug '
Genasense'. The strong correlation of LDH-5 expression with Mcl-1 expression suggests that treatment strategies inhibiting the activity of Mcl-1 in
melanoma patients should be investigated.