Activation of the p38MAPK signaling pathway and over-expression of Bcl-2/Bcl-_XL in patients with DLBCL: potential biomarkers and targets for therapeutics. A Mexican Lymphoma Group Study

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We have reported in the 2F7 DLBCL cell line that the p38MAPK signaling pathway was activated and correlated with over-expression of the anti-apoptotic gene products Bcl2 and Bcl-_XL. Treatment of 2F7 with rituximab inhibited this signaling pathway and down-regulated Bcl2/Bcl-_XL expression. Over expression of Bcl-2/Bcl-_XL was responsible for chemo-immunoresistance and their down regulation by rituximab were responsible for sensitization to apoptosis by various chemotherapeutic drugs. (See reviews Bonavida and Vega, Drug Resist Updat. 8:27, 2005; Jazirehi and Bonavida, Oncogene. 24:448, 2005). Based on these in vitro findings, we hypothesized that similar findings may be also observed in tissues derived from patients with DLBCL. This hypothesis was tested by immunohistochemistry. This preliminary study examined the expression of Bcl-2, Bcl-_XL and p38 MAPK activity using formalin fixed, paraffin embedded sections from tissues derived from patients with DLBCL, obtained from the Pathology Department of the National Cancer Institute SSA, Mexico. The tissue samples were derived from 39 DLBCL in several stages. Immunohistochemistry was performed for the expression of Bcl-2, Bcl-_XL and phospho-p38 MAPK. The immunostaining was scored for intensity expression, recorded and the data were analyzed statistically. The findings revealed that 27 of 39 tissues (69%) expressed Bcl-2 and 68% expressed Bcl-_XL. Four patients (10%) were negative for both. Eight patients (20%) expressed only Bcl-_XL and 10 patients (25%) expressed only Bcl-2. However, 32 of 39 patients expressed phospho-p38MAPK suggesting a good correlation between the activation of p38MAPK and expression of Bcl-2/Bcl-_XL. There was an inverse relationship between the expression of Bcl-2 and Bcl-_XL. These findings corroborate the in vitro findings with B-NHL cell lines and suggest that over-expression of Bcl-2; Bcl-_XL and p38 MAPK activity may be involved in the pathogenesis of NHL and are potential biomarkers for tumor unresponsiveness to chemo-immune-mediated cytotoxic therapies. Furthermore, inhibitors of Bcl-2, Bcl-_XL or p38 MAPK expression/activity may be targets for therapeutic intervention when combined with chemo-immunotherapy. This work was supported in part by a UCLA Jonsson Comprehensive Cancer Center Fellowship (M.V.), a Fogarty Training Grant (M.V. & S.H.), by IMSS, Mexico (M.V. & S.H.), and CONACyT.