Abstract
Overexpression of the anti-apoptotic protein BCL-2 is characteristic of human follicular lymphoma (FL) and some cases of diffuse large B cell lymphoma (DLBCL). We aimed to determine autophagy status in primary FL and DLBCL samples and the BCL-2+/BCL-2- lymphoma cell lines using both autophagy PCR array and tissue microarray (TMA). A greater number of autophagy machinery genes were up-regulated in the BCL-2+ Su-DHL4 cell line compared with BCL-2- Su-DHL8 cells, at both the basal level and in response to autophagic stress. The autophagy-related gene expression profiles were determined in purified and unpurified malignant human lymph node biopsies. Seven autophagy machinery genes were up-regulated in purified FL B-cells compared with reactive B-cells. Only 2 autophagy machinery genes were up-regulated in DLBCL B-cells. In unpurified tissue biopsies, 20 of 46 genes in FL and 2 of 5 genes in DLBCL with increased expression were autophagy machinery genes. Expression of autophagy substrates p62 and LC3 were determined by TMAs. FL samples showed significantly decreased levels of both p62 and LC3 compared with reactive and DLBCL, indicative of an increased autophagy activity in FL. In summary, these results demonstrate that FL showed increased basal autophagy activity, regardless of overexpression of BCL-2 in this disease.
Highlights
Macroautophagy is a physical and pathological process that allows eukaryotic cells sequester portions of cytoplasm to form autophagosomes and target them for degradation through the fusion of autophagosomes with lysosomes where they are degraded and recycled [1,2,3,4]
To evaluate the impact of BCL-2 overexpression on autophagy in human lymphoma, we first compared the autophagy status of the BCL-2+ Su-DHL4 with the BCL2- Su-DHL8 diffuse large B-cell lymphoma (DLBCL) cell lines using Western blotting and the RT2 Profiler PCR array (Figure 1)
We report that Follicular lymphoma (FL), an indolent non-Hodgkin lymphomas (NHLs) which frequently overexpresses the anti-apoptotic protein BCL-2, showed significantly increased expression of www.impactjournals.com/oncotarget key autophagy genes and decreased levels of autophagy substrate protein p62 and LC3 compared with RA B-cell controls
Summary
Macroautophagy (hereafter referred to as autophagy) is a physical and pathological process that allows eukaryotic cells sequester portions of cytoplasm to form autophagosomes and target them for degradation through the fusion of autophagosomes with lysosomes where they are degraded and recycled [1,2,3,4]. Growing evidence demonstrates that autophagy plays important and paradoxical roles in tumorigenesis and in the treatment of cancer [4,5,6,7]. Induction of autophagy by metabolic stress in apoptosis deficient tumor cells can support tumor cell survival [8]. The t(14;18)(q32;q21) translocation characterizes approximately 85% of FL and 20% of diffuse large B-cell lymphoma (DLBCL) and results in constitutive overexpression of the anti-apoptotic protein BCL-2 [14, 15]. Overexpression of BCL-2 in NHLs plays important roles in disease pathogenesis and resistance to apoptosis. It is currently unknown whether BCL-2 plays an important role in regulation of autophagy in indolent FL and more aggressive DLBCL
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