SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas

Chen, Linfeng; Monti, Stefano; Juszczyński, Przemysław; Ouyang, Jing; Chapuy, Bjoern; Neuberg, Donna; Doench, John G.; Bogusz, Agata M.; Habermann, Thomas M.; Doğan, Ahmet; Witzig, Thomas E.; Kutok, Jeffery L.; Rodig, Scott J.; Golub, Todd R.; Shipp, Margaret A.

doi:10.1016/j.ccr.2013.05.002

Cited by 150 publications

(202 citation statements)

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“…Unexpectedly, we failed to detect a perceptible change in terms of the expression for total and activated (phosphorylated) ERK1/2, p38 and JNK, suggesting that MAP kinases are not relevant to an aloperinemediated protective effect in our model. These re sults prompted us to embark on the PI3K/ Akt/mTOR signaling, which is well known to regulate a variety of essential cellular functions ranging from glucose metabolism, protein synthesis, cell proliferation, apoptosis and survival (55)(56)(57)(58). PI3K consists of two elements, the regulatory subunit p85 and the cat alytic subunit p110 (22,59).…”

Section: Discussionmentioning

confidence: 99%

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Zhang

et al. 2015

Mol Med

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Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1β and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-β expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.

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Section: Discussionmentioning

confidence: 99%

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Zhang

et al. 2015

Mol Med

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“…Mitochondria isolated from three independent OxPhos-and three nonOxPhos/BCR-DLBCL cell lines were analyzed using this platform. The DLBCL subtype designation of these cells lines based on the CCC and COO classifications has been previously reported 13,16,26,27 (Supplementary Information). The DEEP SEQ platform not only quantified the enrichment of mtDNA-encoded ETC subunits in OxPhos-DLBCLs compared with BCR counterparts but also revealed significantly higher levels of numerous protein components of the mitochondrial translation machinery (Figures 1a-e; Table 1; Supplementary Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

“…14,15 COO and CC classifications capture different aspects of DLBCL biology. For example, CCC-defined BCR-DLBCLs include BCR-dependent tumors of both ABC and GCB COO subtypes, 16,17 whereas CC-classified OxPhos-DLBCLs include BCRindependent tumors. 7,16 Our previous functional analyses of DLBCL subtypes also uncovered quantitative proteome-and metabolome-level signatures associated with differences in nutrient and energy metabolism.…”

mentioning

confidence: 99%

“…For example, CCC-defined BCR-DLBCLs include BCR-dependent tumors of both ABC and GCB COO subtypes, 16,17 whereas CC-classified OxPhos-DLBCLs include BCRindependent tumors. 7,16 Our previous functional analyses of DLBCL subtypes also uncovered quantitative proteome-and metabolome-level signatures associated with differences in nutrient and energy metabolism. 7 Specifically, these studies showed that BCR-dependent DLBCLs have greater glycolytic flux typical of the Warburg phenotype.…”

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confidence: 99%

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Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

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BH3 ‐Only Proteins

Tuzlak

2016

Encyclopedia of Life Sciences

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The deregulation of programmed cell death, apoptosis, is a major contributor to the development of diseases, including cancer or autoimmunity, and can impair the response of transformed cells to therapy. The Bcl‐2 family of proteins includes critical regulators of the intrinsic apoptosis pathway. BH3 (Bcl‐2 homologous 3)‐only proteins are proapoptotic members that share with each other and the wider Bcl‐2 family only the ‘BH3 domain’. This short stretch of about 16 amino acids is necessary for protein–protein interaction that is critical for their apoptosis‐inducing capacity. BH3‐only proteins promote cell death by regulating activation of Bax and Bak, in a cell‐type and stimulus‐specific manner. Studies of gene‐targeted mice that lack two or more BH3‐only proteins have helped to unravel the overlapping functions of these apoptosis initiators. With the dawn of CRISPR/Cas9 gene‐editing technologies, this strategy was taken even further, opening up allegedly answered questions again, at least at the cellular level. BH3 mimetics were recently approved for the treatment of patients suffering from cancer and it can be anticipated that these drugs make second use to treat autoimmunity and ageing‐related disorders in the future. Key Concepts The ‘Bcl‐2‐regulated’ (also called ‘intrinsic’ or ‘mitochondrial’) apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation and γ‐irradiation) and is regulated by the interplay of the pro‐ and antiapoptotic members of the Bcl‐2 family of proteins controlling integrity of the outer mitochondrial membrane (OMM). The survival versus death fate of a cell is decided not only by the relative levels of pro‐ and antiapoptotic Bcl‐2 family members, but also depends on their ‘activation status’, frequently imposed by different posttranslational modifications on these proteins. Abnormal cell survival during establishment and maintenance of immune‐(self)‐tolerance as well as defects in apoptosis signalling at the end of an immune response may lead to neoplastic transformation and tumourigenesis. The Bcl‐2 family consists of three subgroups of proteins that can be differentiated based on amino acid sequence, 3D structure and function. Bcl‐2, Bcl‐xL, Bcl‐w, Bcl‐B, Mcl‐1 and A1 are essential for cell survival, with cell‐type‐specific expression, while Bcl‐B is found active only in humans. The two other, proapoptotic, subfamilies encompass the multi‐BH domain Bcl‐2 family members Bax, Bak and Bok as well as the BH3‐only protein subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa/Pmaip, Bmf and Puma/Bbc3. The BH3‐only proteins are critical activators of the effector phase of the intrinsic death pathway, while Bax and Bak act as executers of apoptosis by initiating mitochondrial outer membrane permeabilisation (MOMP). The role of Bok in this group remains to be clarified in full. Both Puma and Noxa, apoptosis initiators that can be transcriptionally activated by p53 in response to DNA damage or oncogenic stress, can act as tumour suppressors in their own right, particularly in the context of an oncogenic lesion that subverts cell cycle control. Yet, in most circumstances tested, Puma appears more effective, suggesting roles for Noxa outside the p53 response. Bid functions as the link between the ‘death receptor’ and the ‘Bcl‐2‐regulated’ apoptotic pathways by causing an amplification of the caspase cascade that leads to cell destruction. Remarkably, Bid is critical for Fas ‘death receptor’‐induced apoptosis in certain cell types, such as hepatocytes, but dispensable in others, including lymphoid cells. Additional roles of Bid, downstream of other proteases, have been suggested. Bim, the most studied BH3‐only protein, is critical for many physiologic and pathologic cell death processes and is a principal regulator of homeostasis in the lymphoid and myeloid compartment. Bim is crucial for the negative selection of autoreactive immature T‐ and B‐lymphoid cells and for growth factor deprivation‐induced apoptosis of many cell types. Loss of BIM in certain human cancers substantiates its role as a tumour suppressor and ample data supports a key role in anticancer therapy. Additional BH3‐only proteins such as Bmf, Bad, Hrk and Bik are less well studied and poorly understood. Available data suggests that they support the key effectors Bim, Puma or Bid in potentiating cell killing in a cell‐type and stimulus‐dependent manner. Functions outside canonical apoptosis signalling remain plausible. BH3‐only proteins have a crucial function in chemotherapeutic drug‐induced killing of tumour cells and their loss is frequently associated with resistance to anticancer therapy. Some proteins are equally important in killing autoreactive immune cells or can become aberrantly activated in chronic inflammatory or degenerative disorders, contributing to diverse pathologies. Mimicking BH3‐only proteins represents a promising strategy for enhancing the effects of conventional anticancer therapy and for treating autoimmune diseases, whereas the blockade of these proteins may be beneficial in the management of certain degenerative diseases that are characterised by abnormal killing of cells that should be kept alive.

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SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas

Cited by 150 publications

References 50 publications

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

BH3 ‐Only Proteins

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