The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor

Case, Kendall C.; Schmidtke, Michael W.; Greenberg, Miriam L.

doi:10.1007/s10555-022-10032-8

Cited by 7 publications

(2 citation statements)

References 14 publications

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“…In benign tissues close to aggressive tumors, the levels of myo-inositol were also elevated. This metabolite is involved in many biological processes ranging from intracellular signal transduction, calcium homeostasis regulation to energy metabolism, and it is essential for cancer formation and metastasis (35, 36). Using prostate tissue extracts, inositol hexaphosphate (IP6) was shown to significantly decrease glucose metabolism and membrane phospholipid synthesis, in addition to causing an increase in myo-inositol levels in the prostate (37).…”

Section: Discussionmentioning

confidence: 99%

Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

Dudka,

Wikström,

Bergh

et al. 2024

Preprint

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Background: Prostate cancer (PC) diagnosis relies on histopathological examination of prostate biopsies, which is restricted by insufficient sampling of all tumors present. Including samples from non-PC but tumor instructed normal tissues (TINT) may increase the diagnostic power by exploring the adaptive responses in benign tissues near tumors. Methods: Here, we applied high-resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) to identify metabolomic biomarkers with high diagnostic value in benign prostate tissues near low/high-grade tumors. Results: Benign samples near high-grade tumors (B ISUP 3+4) exhibit altered metabolic profiles compared to those close to low-grade tumors (B ISUP 1+2). The levels of six metabolites were significantly different between the two groups; myo-inositol, lysine, serine and combined signal of lysine/leucine/arginine were increased in benign samples near high-grade tumors (B ISUP 3+4) compared to near low-grade tumors (B ISUP 1+2), while levels of ethanolamine and lactate decreased. Additionally, we revealed metabolic differences in non-cancer tissues as a function of their distance to the nearest tumor. Eight metabolites (glutathione, glutamate, combined signal of glutamate/glutamine - glx, glycerol, inosine, ethanolamine, serine and arginine) significantly differentiated between benign tissue located close to the tumor (d ≤ 5 mm) compared to those far away (d ≥ 1 cm). Conclusions: Our HR MAS NMR-based approach identified metabolic signatures in prostate biopsies that reflect the response of benign tissues to the presence of nearby located tumors in the same prostate and confirmed the power of the TINT concept for improved PC diagnostics and understanding of tumor-tissue interactions.

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Section: Discussionmentioning

confidence: 99%

Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

Dudka,

Wikström,

Bergh

et al. 2024

Preprint

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“…Myo -inositol (referred to as inositol in this article) is the most abundant inositol isoform. This six-carbon cyclitol sugar is the precursor to inositol-containing lipids and soluble inositol phosphates 1 , 2 , which play extensive roles in cellular regulatory mechanisms, including DNA transcriptional regulation 2 – 4 , metabolism 1 , 2 , 5 , 6 , organelle membrane labeling and trafficking 7 , 8 , signal transduction 1 , 6 , 8 , and others. Disequilibrium of inositol levels is associated with a significant number of diseases 1 , which is unsurprising considering its extensive role in regulatory pathways.…”

Section: Introductionmentioning

confidence: 99%

Valproate regulates inositol synthesis by reducing expression of myo-inositol-3-phosphate synthase

Case,

Beltman,

Pflum

et al. 2023

Sci Rep

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Inositol depletion is a hypothesized mechanism of action of mood stabilization drugs used in the treatment of bipolar disorder. It was previously reported that the mood stabilizer valproate (VPA) increased phosphorylation of myo-inositol-3-phosphate synthases (MIPS), the rate limiting enzyme of inositol synthesis. Phosphosites were identified and examination of site-directed mutants suggested that phosphorylation leads to decreased enzymatic activity. In this study, we examined the extent of MIPS phosphorylation in response to VPA and used two interaction screens to identify protein kinases that interact with MIPS. Using an epitope tagged MIPS construct, we determined the fraction of phosphorylated MIPS to be very low (less than 2% of total), and we could not detect phosphorylation of untagged MIPS in response to VPA. In vitro analyses of phosphorylation revealed that putative protein kinases, PKC and CKII, have low specificity toward MIPS. These findings suggest that VPA likely depletes inositol via a mechanism other than MIPS phosphorylation. Consistent with this, mRNA levels of the MIPS-encoding gene INO1 and MIPS protein levels were significantly reduced during the mid-log growth phase in response to VPA treatment. These findings suggest that the mechanism whereby VPA causes inositol depletion is by reducing expression of the rate-limiting enzyme MIPS.

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Emerging role of inositol monophosphatase in cancer

Chen¹,

Shen²,

Li³

2023

Biomedicine & Pharmacotherapy

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The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor

Cited by 7 publications

References 14 publications

Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

Valproate regulates inositol synthesis by reducing expression of myo-inositol-3-phosphate synthase

Emerging role of inositol monophosphatase in cancer

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