Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

Murali, Roopak; Balasubramaniam, Vaishnavi; Srinivas, Satish; Sundaram, Sandhya; Venkatraman, Ganesh; Warrier, Sudha; Dharmarajan, Arun; Gandhirajan, Rajesh Kumar

doi:10.3390/metabo13040560

Cited by 11 publications

(8 citation statements)

References 282 publications

(309 reference statements)

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“…This analysis suggested an increase in metabolic pathways such as ketogluconate metabolism and the superpathway of glycerol degradation to 1,3-propanediol, while pathways including the superpathway of fatty acid biosynthesis initiation and phospholipases were predicted to decrease in the estropausal group (Figure 1F). These predicted metabolic changes, including an increase in ketoglutarate and alterations in lipid metabolism, have been previously associated with ovarian cancers, underscoring the potential relevance of our findings to understanding ovarian health 43,44 . Our results collectively underscore the pronounced differences in the fecal microbial profiles between young and estropausal females.…”

Section: Resultssupporting

confidence: 70%

Estropausal gut microbiota transplant improves ovarian function in adult mice

Kim,

Wang,

et al. 2024

Preprint

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Decline in ovarian function with age not only affects fertility but is also linked to a higher risk of age-related diseases in women (e.g. osteoporosis, dementia). Intriguingly, earlier menopause is linked to shorter lifespan; however, the underlying molecular mechanisms of ovarian aging are not well understood. Recent evidence suggests the gut microbiota may influence ovarian health. In this study, we investigated the effect of the gut microbiome from young and estropausal female mice on ovarian health through fecal microbiota transplantation. We demonstrate that the ovarian transcriptome can be broadly remodeled after heterochronic microbiota transplantation, with a reduction in inflammation-related gene expression and trends consistent with transcriptional rejuvenation. Consistently, these mice exhibited enhanced ovarian health and increased fertility. We also identified candidate microbial genera potentially responsible for the observed transcriptomic changes through causal mediation analyses. Our findings reveal a direct link between the gut microbiota and ovarian health.

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Section: Resultssupporting

confidence: 70%

Estropausal gut microbiota transplant improves ovarian function in adult mice

Kim,

Wang,

et al. 2024

Preprint

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“…Interestingly, the upregulation of Acly, Acsl4, Gpd2 but downregulation of Pfkl suggests a shift in MOSE-L TICv metabolism from glycolysis to other energy substrates. Increased fatty acid synthesis during progression was also observed in the MOSE model [33] and has been shown to be critical for tumor growth (see recent review [34]).…”

Section: Mose-l + Svfmentioning

confidence: 87%

Genetic and Functional Modifications Associated with Ovarian Cancer Cell Aggregation and Limited Culture Conditions

Grieco,

Compton,

Davis

et al. 2023

IJMS

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The aggregation of cancer cells provides a survival signal for disseminating cancer cells; however, the underlying molecular mechanisms have yet to be elucidated. Using qPCR gene arrays, this study investigated the changes in cancer-specific genes as well as genes regulating mitochondrial quality control, metabolism, and oxidative stress in response to aggregation and hypoxia in our progressive ovarian cancer models representing slow- and fast-developing ovarian cancer. Aggregation increased the expression of anti-apoptotic, stemness, epithelial-mesenchymal transition (EMT), angiogenic, mitophagic, and reactive oxygen species (ROS) scavenging genes and functions, and decreased proliferation, apoptosis, metabolism, and mitochondrial content genes and functions. The incorporation of stromal vascular cells (SVF) from obese mice into the spheroids increased DNA repair and telomere regulatory genes that may represent a link between obesity and ovarian cancer risk. While glucose had no effect, glutamine was essential for aggregation and supported proliferation of the spheroid. In contrast, low glucose and hypoxic culture conditions delayed adhesion and outgrowth capacity of the spheroids independent of their phenotype, decreased mitochondrial mass and polarity, and induced a shift of mitochondrial dynamics towards mitophagy. However, these conditions did not reduce the appearance of polarized mitochondria at adhesion sites, suggesting that adhesion signals that either reversed mitochondrial fragmentation or induced mitobiogenesis can override the impact of low glucose and oxygen levels. Thus, the plasticity of the spheroids’ phenotype supports viability during dissemination, allows for the adaptation to changing conditions such as oxygen and nutrient availability. This may be critical for the development of an aggressive cancer phenotype and, therefore, could represent druggable targets for clinical interventions.

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“…For a detailed and up-to-date review of ovarian cancer and metabolism, see ref. [94]. Many ovarian cancer cells favor energy production, primarily by glycolysis over mitochondrial OXPHOS, but some cancer cells behave distinctly in the opposite way.…”

Section: Factors That Influence Energy Metabolismmentioning

confidence: 99%

Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

Kobayashi,

Yoshimoto,

Matsubara

et al. 2023

JMP

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Background: Ovarian cancer is often characterized by aggressive growth and chemoresistance, leading to a poor prognosis. The energy and nutrient acquisition through metabolic reprogramming has been reported to facilitate cancer cell proliferation, invasion, and metastasis. Therefore, a therapeutic strategy to consider is to rewire energy metabolism. Mitochondrial dynamics have a profound impact on the metabolic profiles. In this review, we summarize the current understanding of the molecular mechanisms governing mitochondrial dynamics and their impact on cell proliferation and invasion and discuss future perspectives for therapeutic strategies and research directions. Methods: A search was conducted for literature published up to 30 June 2023 using the online databases PubMed and Google Scholar in this narrative literature review. Results: Mitochondria are essential for regulating metabolic reprogramming to meet the increasing energy demand for rapid cancer cell proliferation and invasion. A metabolic switch from OXPHOS to glycolysis may promote invasion, and OXPHOS-driven metabolism may be associated with proliferation, chemoresistance, and stemness. Many ovarian cancer cells are known to favor glycolysis over OXPHOS, but the opposite takes place in the subpopulation of cancer cells. The preference for glycolysis versus OXPHOS in ovarian cancer cells may be determined by histopathologic types, the unique genetic profile of energy metabolism, and intrinsic (e.g., oncogenic signaling) and extrinsic (e.g., nutritional status and hypoxia) factors. Conclusions: Preclinical studies suggest that mitochondrial dynamics regulators have therapeutic potential in ovarian cancer, but some factors limit their beneficial effects.

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Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

Cited by 11 publications

References 282 publications

Estropausal gut microbiota transplant improves ovarian function in adult mice

Estropausal gut microbiota transplant improves ovarian function in adult mice

Genetic and Functional Modifications Associated with Ovarian Cancer Cell Aggregation and Limited Culture Conditions

Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

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