Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia

Saito, Yûsuke; Kinoshita, Mariko; Yamada, Akihiro; Kawano, Sayaka; Liu, Hongshan; Kamimura, Sachiyo; Nakagawa, Mayu; Nagasawa, Syun; Taguchi, Tadao; Yamada, Shuhei; Moritake, Hiroshi

doi:10.1111/cas.15138

Cited by 26 publications

(13 citation statements)

References 39 publications

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“…Our data show that targeting MPI and MM sensitizes AML cells to AraC and FLT3-TKI. Recent reports, including one in leukaemic cells 48 , suggest that MPI could be a therapeutic target in cancer therapy 22 , 23 . Most of these reports however suggest that MPI inhibition would limit the ability of cancer cells to withstand the toxicity of an exogenous high-dose mannose diet.…”

Section: Discussionmentioning

confidence: 99%

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

et al. 2023

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Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

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Section: Discussionmentioning

confidence: 99%

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

et al. 2023

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“…Our data show for the first time that targeting MPI and MM sensitizes AML cells to AraC and FLT3-TKI. Recent reports, including one in leukemic cells 45 , suggest that MPI could be a therapeutic target in cancer therapy 22,23 . Most of these reports however suggest that MPI inhibition would limit the ability of cancer cells to withstand the toxicity of an exogenous high-dose mannose diet.…”

Section: Discussionmentioning

confidence: 99%

Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death

Woodley

Dillingh

Giotopoulos

et al. 2022

Preprint

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Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a novel connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

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“…Similarly, polysaccharides with amounts of uronic acid were beneficial to its hepatoprotective activity ( 18 ). In addition, the polysaccharides containing mannose and rhamnose were proved to have tumor-inhibitory and antioxidant activities, individually ( 23 , 24 ). However, the specific rules and mechanisms have not been clearly set forth and need further exploration.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

Structural Elucidation, Modification, and Structure-Activity Relationship of Polysaccharides in Chinese Herbs: A Review

et al. 2022

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Chinese herbal polysaccharides (CHPs) are natural polymers composed of monosaccharides, which are widely found in Chinese herbs and work as one of the important active ingredients. Its biological activity is attributed to its complex chemical structure with diverse spatial conformations. However, the structural elucidation is the foundation but a bottleneck problem because the majority of CHPs are heteropolysaccharides with more complex structures. Similarly, the studies on the relationship between structure and function of CHPs are even more scarce. Therefore, this review summarizes the structure-activity relationship of CHPs. Meanwhile, we reviewed the structural elucidation strategies and some new progress especially in the advanced structural analysis methods. The characteristics and applicable scopes of various methods are compared to provide reference for selecting the most efficient method and developing new hyphenated techniques. Additionally, the principle structural modification methods of CHPs and their effects on activity are summarized. The shortcomings, potential breakthroughs, and developing directions of the study of CHPs are discussed. We hope to provide a reference for further research and promote the application of CHPs.

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Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia

Cited by 26 publications

References 39 publications

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death

Structural Elucidation, Modification, and Structure-Activity Relationship of Polysaccharides in Chinese Herbs: A Review

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