Dataset Information

Proteomic-based analysis of hypoxia and physioxia responsive proteins and pathways in DLBCLProteomic-based analysis of hypoxia and physioxia responsive proteins and pathways in DLBCL

ABSTRACT: Hypoxia is damaging to normal cells as well as cancerous cells. Reports assessing hypoxia- and physioxia-induced global proteome changes in lymphoma are lacking. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to the acute hypoxic stress (1% of O2) and the 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 have significant changes in abundance in 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 down-regulation 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, down-regulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of up-regulated 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 varia-ble oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL, potentially important in developing more aggressive phenotype.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jacek Wisniewski

LAB HEAD: Jacek R. Wisniewski

PROVIDER: PXD026726 | Pride | 2022-02-17

REPOSITORIES: Pride

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			Action	DRS
	20190131_QX7_JRW_SA_L_JJ01_190314090040.raw	Raw
	20190131_QX7_JRW_SA_L_JJ02.raw	Raw
	20190131_QX7_JRW_SA_L_JJ03.raw	Raw
	20190131_QX7_JRW_SA_L_JJ04.raw	Raw
	20190131_QX7_JRW_SA_L_JJ05.raw	Raw

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Publications

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma.

Duś-Szachniewicz Kamila K Gdesz-Birula Katarzyna K Zduniak Krzysztof K Wiśniewski Jacek R JR

Cells 20210808 8

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 O<sub>2</sub>) and physioxia (5% of O<sub>2</sub>) for a long-time. A total of 8239 proteins were identified by LC-MS/MS, of which 718, 513, and 486 had significant changes, ...[more]

PMID: 34440794

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Project description:Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of HIF1α resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using 35S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of HK2 in B-cell lymphoma development and suggest that HK2 is a key metabolic driver of the DLBCL phenotype.ne incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely blunted and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with decrease in mitochondrial function. Screening of DLBCL patient samples identified that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies show that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide more definitive proof of direct contribution of HK2 in development of B-cell lymphoma and suggest that HK2 is a key metabolic driver of DLBCL phenotype.