Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death

Lee, Eric A; Angka, Leonard; Rota, Sarah-Grace; Hanlon, Thomas; Mitchell, Anne; Hurren, Rose; Wang, Xiao Ming; Gronda, Marcela; Boyacı, Ezel; Bojko, Barbara; Minden, Mark D.; Sriskanthadevan, Shrivani; Datti, Alessandro; Wrana, Jeffery L.; Edginton, Andrea N.; Pawliszyn, Janusz; Joseph, Jamie W.; Quadrilatero, Joe; Schimmer, Aaron D.; Spagnuolo, Paul A.

doi:10.1158/0008-5472.can-14-2676

Cited by 145 publications

(146 citation statements)

References 45 publications

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“…Inhibition of FAO increases sensitivity to apoptosis in cell culture and in a murine model of human AML (Estañ et al, 2014; Lee et al, 2015). Furthermore, FAO was shown to be critical for maintenance of hematopoietic stem cells, and was suggested to be involved in the maintenance of leukemic initiation cells (Ito et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

et al. 2016

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SUMMARY While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.

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Section: Resultsmentioning

confidence: 99%

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

et al. 2016

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“…Of note, during the metabolic shift towards FAO, activation of autophagy hydrolyzes lipids into fatty acids for fuel [58]. Considering that FAO is an important source of NADPH in leukemic cells [59], we examined whether rates of FAO were increased in carfilzomib-resistant LP-1/Cfz and KMS-11/Cfz cells. Increased FAO was observed in LP-1/Cfz versus parental LP-1 cells (Figure 3A, 3B).…”

Section: Resultsmentioning

confidence: 99%

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

et al. 2016

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Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients.

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“…Avocatin B, a lipid derived from the avocado fruit, is one example of a novel compound. Avocatin B blocks fatty acid oxidation, and reduces NADPH levels, in primary human leukemia cells, resulting in ROS-dependent cell death [111]. This cytotoxicity depends upon both mitochondrial localization of Avocatin B and functional expression of CPT1α.…”

Section: Therapeutic Targeting Of Metabolic Pathwaysmentioning

confidence: 99%

Targeting immuno-metabolism to improve anti-cancer therapies

Beezhold

Byersdorfer

2018

Cancer Letters

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The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism. Research over the last decade has revealed that T cell proliferation and differentiation is intimately linked to robust changes in metabolic activity, delineation of which may provide ways to manipulate the immuno-oncologic responses to our advantage. Here, we provide a basic overview of T cell metabolism, discuss what is known about metabolic regulation of T cells during allogeneic HSCT, point to evidence on the importance of T cell metabolism during CAR T cell and solid tumor therapies, and speculate about the role for compounds that might have dual-action on both immune cells and tumor cells simultaneously.

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Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death

Cited by 145 publications

References 45 publications

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

Targeting immuno-metabolism to improve anti-cancer therapies

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