Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis

Li, Meng; Chiang, Ying-Ling; Lyssiotis, Costas A.; Teater, Matt; Hong, Jun Young; Shen, Hao; Wang, Ling; Hu, Jing; Jing, Hui; Chen, Zhengming; Jain, Neeraj; Duy, Cihangir; Mistry, Sucharita J.; Cerchietti, Leandro; Cross, Justin R.; Cantley, Lewis C.; Green, Michael R.; Lin, Hening

doi:10.1016/j.ccell.2019.05.002

Cited by 90 publications

(125 citation statements)

References 84 publications

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“…We found that HK2‐inducible autophagy is “oncogenic” in MM, particularly in myeloma cells in the hypoxic bone marrow microenvironment. In other hematopoietic tumors, such as diffuse large B‐cell lymphoma, autophagy can also act as a tumor suppressor 44 . In contrast, the oncogenic autophagy mechanism is likely to be myeloma specific because, unlike other cancers, myeloma cells are exposed to intense ER stress caused by large amounts of non‐functional monoclonal proteins.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

et al. 2020

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Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco‐biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia‐inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI‐resistant myeloma cells. Here, a hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti‐apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2‐knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3‐bromopyruvate (3‐BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3‐BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM.

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

et al. 2020

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“…SIRT3 can deacetylate IDH2 to increase its activity in promoting carcinogenesis 107 . In diffuse large B cell lymphomas (DLBCLs), SIRT3 was proven to accelerate TCA cycle metabolism via enhancing GDH activity to promote lymphomagenesis 108 . Not surprisingly, SIRT3 has also been found to promote tumor progression in some other cancers.…”

Section: Sirt3 and Human Diseasementioning

confidence: 99%

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Zhang¹,

Xiang²,

Liu³

et al. 2020

Theranostics

271

238

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Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.

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“…In work reported during the finalization of our study, a commonly used mitochondrial targeting motif (the triphenylphosphonium group) was attached to a SIRT2 inhibitor, to inhibit SIRT3 in the mitochondria rather than SIRT1 and SIRT2 in the nucleus and cytosol, respectively. [58] The chemotypes developed in the present study, however, have a fundamentally different architecture and includes optimization of their selectivity profiles to dial down affinity for SIRT1 and SIRT2. Our design was predicated on the fusion of attributes from mechanism-based class I sirtuin inhibitors with mitochondria-targeting peptides.…”

Section: Resultsmentioning

confidence: 99%

Mitochondria-Targeted Inhibitors of the Human SIRT3 Lysine Deacetylase

Troelsen¹,

Bæk²,

Nielsen³

et al. 2020

Preprint

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<p>Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in the mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as a potential drug target in certain cancers. Investigation of pharmacological intervention has been challenging due to a lack of potent and selective inhibitors of SIRT3. Here, we developed a strategy for selective inhibition of SIRT3 in cells, over its structurally similar isozymes that localize primarily to nucleus (SIRT1) and cytoplasm (SIRT2). This was achieved by directing the inhibitors straight to the mitochondria through incorporation of sequences inspired by previously described mitochondria-targeting peptides. Our inhibitors exhibited excellent mitochondrial localization in HeLa cells as indicated by fluorophore-conjugated versions and target engagement was demonstrated by a thermal shift assay of SIRT3 using western blotting. The acetylation state of documented SIRT3 target MnSOD was shown to be perturbed in cells with little effect on known targets of SIRT1 and SIRT2, showing that our lead compound exhibits selectivity for SIRT3 in cells. We expect that the developed inhibitor will now enable a more detailed investigation of SIRT3 as a potential drug target and help shed further light on the diverse biology regulated by this enzyme. </p>

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Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis

Cited by 90 publications

References 84 publications

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

Hypoxia‐inducible hexokinase‐2 enhances anti‐apoptotic function via activating autophagy in multiple myeloma

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Mitochondria-Targeted Inhibitors of the Human SIRT3 Lysine Deacetylase

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