Abstract
Abstract 1555
Poster Board I-578
Current therapeutic regimen for classical Hodgkin lymphoma (HL) includes the combined ABVD chemotherapy often followed by radiotherapy. Albeit HL is, in many cases, a curable malignancy, several issues still pose serious threats to the patients. For instance late toxicities, chemoresistance insurgence and relapses represent open and unresolved challenges. We are currently investigating the molecular response of lymphoid cells to doxorubicin treatment and ionizing radiation (IR) in an experimental model represented by HL-derived cell lines. We show the expression and modulation of the stress-inducible protein clusterin/XIP8 (clusterin) in lymphoid cells. The nuclear isoform (having a MW of about 55kDa) is up-regulated upon doxorubicin treatment starting at a concentration of 0.5 micromolar. Interestingly enough, also interferon-gamma determines clusterin and p53 up-regulation starting at 50 nanograms/ml even though just a modest cytostatic effect is observed with this cytokine. High doses of IR increase intracellular clusterin levels, extending to lymphomas a phenomenon first described in the breast carcinoma cell line MCF-7. p53 and Bax are also up-regulated by 12Gy IR at the different time points studied, consistently with the activation of the intrinsic apoptotic pathway. A long-lasting, intracellular clusterin up-regulation observed in surviving cells following irradiation (up to 72h) suggests that this protein is part of the IR-triggered adaptive response. The three cell lines tested here (L-428, KM-H2 and L-540) feature different caspase-3 activity levels. By means of the caspase-3 inhibitor Ac-DEVD-CHO we show here that, in the caspase-3 deficient KM-H2, clusterin is up-regulated by doxorubicin independently of the inhibitor. On the contrary, L-540 shows a different isoforms' expression profile when treated with doxorubicin with or without Ac-DEVD-CHO. This suggests that a linkage exists between caspase-3 activity and clusterin expression.
No relevant conflicts of interest to declare.
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