The Role of MPI and Honeybee Syndrome in Genomic Instability: Implications for Cancer Therapy

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The interconversion between Fruc-6-P and Man-6-P is a crucial metabolic process in mammals, catalyzed by the enzyme MPI (mannose phosphate isomerase).

This enzymatic conversion plays a central role in the synthesis of GDP-mannose, which is essential for normal glycosylation. While the conversion of Fruc-6-P to Man-6-P mediated by MPI is well understood, the reverse conversion from Man-6-P to Fruc-6-P has long puzzled researchers due to its seemingly wasteful nature. However, recent studies have shed light on the significance of this pathway in cellular metabolism and its implications in cancer biology.

Honeybee Syndrome and Genomic Instability

In this study, researchers employed MPI-KO (MPI knockout) human cancer cells to investigate the mechanism behind the anticancer activity of mannose. The researchers observed that the large influx of mannose, exceeding the capacity to metabolize it, led to a condition termed honeybee syndrome.

This condition triggered a series of metabolic remodeling events, resulting in ATP insufficiency and loss of deoxynucleotide triphosphates (dNTPs), the building blocks of DNA. As a consequence, the cells experienced replication stress and were unable to rescue stalled replication forks, exacerbating genomic instability.

Metabolic Remodeling and Cell Cycle Dysregulation

The findings of this study highlight the intricate crosstalk between metabolic networks and the cell cycle machinery. The dysregulation of normal mannose catabolism, caused by honeybee syndrome, disrupts bioenergetic states and cell cycle progression.

Excess mannose inhibits glycolysis, retards cell proliferation, and impairs the progression of replication forks, leading to abnormal cell cycle progression. These observations emphasize the critical role of balanced mannose metabolism in maintaining cellular homeostasis.

MPI Expression and Antiproliferative Effects

The antiproliferative effect of mannose was found to be largely dependent on the expression levels of MPI in human cancer cell lines. The absence of MPI resulted in unique genomic instability phenotypes, suggesting that the clinical use of mannose to induce genomic instability in cancer cells is currently unlikely.

However, the study revealed that pharmacological inhibition of de novo dNTP synthesis, crucial for recovery from replication stress, partially mimicked the anticancer activity of mannose. This finding suggests that targeting dNTP metabolism could be a potential therapeutic strategy independent of MPI expression levels.

Loss of dNTPs in Honeybee Syndrome

The regulation of dNTP pool size is essential to maintain genomic stability. The study found that mannose challenge shifted the equilibrium of dNTP metabolism toward biosynthesis, as indicated by the increased expression of RRM2B, a rate-limiting subunit of ribonucleotide reductase (RNR).

However, despite the upregulation of RRM2B, mannose challenge resulted in substantial reductions in ATP levels, a key allosteric regulator of RNR catalysis. This imbalance, combined with impaired glucose metabolism, severely affected the early stages of de novo purine and pyrimidine nucleotide synthesis, leading to inadequate dNTP pools.

Proteomic Analysis and Honeybee Syndrome

Proteomic analysis of honeybee syndrome revealed several functional pathways affected by the condition. Downregulation of MCM2-7 proteins supported the hypothesis that honeybee syndrome impairs dormant origins and causes genomic instability. Furthermore, mannose challenge influenced ribosomal subunit proteins involved in ribosome biogenesis stress, and it upregulated proteins associated with ferroptosis and necroptosis, mechanisms that can overcome chemoresistance and eliminate apoptosis-resistant cancer cells, respectively.

Conclusion

In summary, this study demonstrates that honeybee syndrome induced by excess mannose triggers dNTP loss and genomic instability in MPI-KO human cancer cells. The findings provide insights into the chemosensitizing effects of mannose and its potential as a therapeutic strategy for poorly proliferating cancer cells.

Further research is needed to fully elucidate the molecular mechanisms underlying dNTP loss in honeybee syndrome and to explore the broader impact of mannose metabolic alterations in cancer cell homeostasis. These investigations may open avenues for mannose-based drug discovery and development for cancer therapy.


in deep…

Genomic instability is a hallmark of cancer, characterized by the accumulation of mutations, chromosomal aberrations, and epigenetic alterations in tumor cells. Genomic instability can arise from defects in DNA repair, replication, or segregation, as well as from exposure to environmental or endogenous sources of DNA damage. Understanding the molecular mechanisms that underlie genomic instability and how they can be exploited for cancer therapy is a major challenge in the field of oncology.

One of the factors that can influence genomic stability is the metabolic enzyme MPI, which catalyzes the interconversion of mannose-6-phosphate and fructose-6-phosphate in the hexose monophosphate shunt pathway. MPI is essential for the synthesis of GDP-mannose, a precursor for glycosylation, a process that modifies proteins and lipids with sugar moieties. Glycosylation plays important roles in cell signaling, adhesion, migration, and immune recognition, and dysregulation of glycosylation has been implicated in various diseases, including cancer.

Mannose Phosphate Isomerase (MPI): Mannose phosphate isomerase (MPI) is an enzyme involved in the metabolism of mannose, a monosaccharide crucial for cellular processes. MPI catalyzes the interconversion of mannose-6-phosphate (M6P) and fructose-6-phosphate (F6P), enabling cells to utilize mannose for various glycosylation reactions and metabolic pathways. Dysregulation of MPI has been associated with several diseases, including MPI-CDG (congenital disorder of glycosylation) and cancer.

MPI deficiency is a rare inherited disorder that causes intellectual disability, seizures, hypoglycemia, and hepatomegaly. Interestingly, MPI deficiency also confers resistance to certain types of cancer, such as lymphoma and leukemia. The mechanism by which MPI deficiency protects against cancer is not fully understood, but it may involve impaired glycosylation of oncogenic proteins or altered immune responses.

Mechanisms Behind MPI Deficiency-Mediated Cancer Protection:

  • Impaired Glycosylation: MPI deficiency leads to a decrease in cellular mannose levels and subsequently affects glycosylation processes. Altered glycosylation patterns have been observed in various cancers and are associated with tumor progression and metastasis. The reduced availability of mannose due to MPI deficiency may disrupt the glycosylation machinery in cancer cells, impairing their ability to undergo essential cellular processes required for tumor growth and survival.
  • Activation of ER Stress Pathways: Endoplasmic reticulum (ER) stress is a cellular response to misfolded proteins and metabolic disturbances. MPI deficiency-induced disruption of glycosylation can trigger ER stress in cancer cells. Activation of the unfolded protein response (UPR) leads to the upregulation of ER stress sensors such as PERK, ATF6, and IRE1. Persistent ER stress and UPR activation ultimately induce cell cycle arrest and apoptosis, limiting the survival and proliferation of cancer cells.
  • Altered Energy Metabolism: Cancer cells exhibit metabolic reprogramming, favoring glycolysis even under normoxic conditions (the Warburg effect). Interestingly, MPI deficiency disrupts the balance between glucose and mannose metabolism, impacting the metabolic flux within cancer cells. Reduced availability of mannose may interfere with glycolysis, leading to impaired ATP production and energy crisis. This metabolic perturbation compromises the survival and growth of cancer cells, creating a hostile environment for tumor development.
  • Modulation of Cellular Signaling Pathways: MPI deficiency has been shown to affect several key signaling pathways involved in cancer progression. One such pathway is the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which regulates cell growth, proliferation, and survival. Studies have demonstrated that MPI deficiency inhibits the activation of PI3K/Akt/mTOR signaling, resulting in the suppression of cancer cell growth and survival. Additionally, MPI deficiency can influence other signaling pathways, including MAPK, Wnt/β-catenin, and Notch, which play critical roles in cancer development.

reference link :https://elifesciences.org/articles/83870#s3

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