Abstract
Hypoxia is a common feature in most tumors, including hematological malignancies. There is a lack of studies on hypoxia- and physioxia-induced global proteome changes in lymphoma. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to acute hypoxic stress (1% of O2) and physioxia (5% of O2) for a long-time. A total of 8239 proteins were identified by LC–MS/MS, of which 718, 513, and 486 had significant changes, in abundance, in the Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant downregulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, downregulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of upregulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a variable oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL. It remains to be investigated whether changes in the proteomes of DLBCL under normoxia and physioxia have functional consequences on lymphoma development and progression.
Highlights
The environment in which lymphoma cells are found in the human body has different levels of oxygenation
We present a report on global protein profiling in diffuse large B-cell lymphoma (DLBCL) cell lines exposed to long-term hypoxia (1%) and physioxia (5%)
This report is the first to investigate the influence of decreased oxygen concentration on the global proteomes of DLBCLB-NHL cell lines
Summary
The environment in which lymphoma cells are found in the human body has different levels of oxygenation. 48 h, lymphoma cells respond to hypoxic stimuli through alterations in gene expression and escape from cell death [5]. Mammalian cells have historically grown and divided well in ambient air, culturing cells in a more physiologic setting concerning oxygen (so-called physioxia) has not received approval for many years. There is strong evidence that physioxia influences the growth [6,7,8], differentiation [9,10], and survival [11] of many cell types, cultured as monolayers and three-dimensional spheroids. Culturing of cells under physiological oxygen has significant consequences on, e.g., adhesion and motility [12], self-renewal [13], and production of EMC and growth factors [14].
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