Abstract
We provide evidence that curcumin, a natural compound isolated from rhizomes of plant Curcuma longa, induces apoptosis in several Burkitt's lymphoma cell lines expressing Bax protein (AS283A, KK124, and Pa682PB), whereas it has no effects in cell lines with no Bax expression (BML895 and CA46). Our data show that curcumin treatment results in down-regulation of constitutive activation of nuclear factor-kappaB (NF-kappaB) via generation of reactive oxygen species where it causes conformational changes in Bax protein leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and poly(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, curcumin treatment of Burkitt's lymphoma cell lines also causes up-regulation of DR5; however, this up-regulation does not result in apoptosis. Importantly, cotreatment with curcumin and TRAIL induces apoptosis in Bax-deficient cell lines. Taken together, our findings suggest that curcumin is able to induce apoptosis in Bax-positive cell lines, whereas combinations with TRAIL result in apoptosis in Bax-negative cell lines. These findings also raise the possibility that incorporation of curcumin in treatment regimens may provide a novel approach for the treatment of Burkitt's lymphomas and provide the molecular basis for such future translational efforts.
Highlights
Burkitt’s lymphoma is a high-grade B-cell lymphoma characterized by a translocation involving the c-myc and immunoglobin gene and has phenotypic features that resemble a germinal center B cell
We sought to determine whether curcumin treatment leads to cell death of Burkitt’s lymphoma cell lines
TUNEL assays as shown in Supplementary Fig. S14 indicated that curcumin treatment resulted in apoptosis in a dose-dependent manner in Bax-positive cell lines only
Summary
Burkitt’s lymphoma is a high-grade B-cell lymphoma characterized by a translocation involving the c-myc and immunoglobin gene and has phenotypic features that resemble a germinal center B cell. Cytochrome c is released to cytosol where along with dATP binds to apoptotic protease-activating factor-1 [12]. This complex, along with adenine nucleotides promotes pro-caspase-9 autoactivation, which in turn activates caspase-3, resulting in poly(ADP)-ribose polymerase (PARP) cleavage. Active caspase-8 cleaves a proapoptotic Bcl-2 family member, Bid, and truncated Bid induces mitochondrial cytochrome c release [13]. A third pathway has been identified, in which Bid is cleaved downstream of the point of Bcl-2 action [15] This event is catalyzed by caspase-3, upstream of caspase-8 activation, and acts as a potential feedback loop for amplification of apoptosis-associated release of cytochrome c from the mitochondria
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