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OA-HOXB9-ODC1-Polyamine Axis Mediates Metabolic Syndrome Promoting Endometrial Cancer Progression

ABSTRACT:

Metabolic syndrome (MS) is a risk factor for both the development and progression of endometrial cancer (EC); however, the mechanism remains unclear. We found that polyamine metabolites are significantly elevated in the sera and tumor tissues of EC patients with MS (ECWMS). Hyperlipidemia is a critical factor in promoting ECWMS, and oleic acid (OA), an important monounsaturated fatty acid, was identified from 12 common fatty acids as a crucial element in upregulating ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine metabolism, and downstream polyamines in the plasma of ECWMS. Mechanistically, OA binds directly to HOXB9 and stabilizes it by preventing its interaction with E3 ligases Praja2. HOXB9 further interacts with ODC1 and competes with the interaction between ornithine decarboxylase antizyme 1 (OAZ1) and ODC1 for proteasomal degradation. The downstream accumulation of polyamine metabolites, especially putrescine, further inhibits the degradation of HOXB9. Targeting the feedback of the HOXB9-ODC1-polyamine axis decreases polyamines and inhibits tumor proliferation and metastasis in vitro and in vivo. Multiplex immunofluorescence staining, liquid chromatography-mass spectrometry (LC-MS), and Raman spectroscopy all demonstrate that the OA-HOXB9-ODC1-polyamine axis is present in ECWMS tissues, and ODC1 inhibitors effectively enhance the sensitivity of patient-derived tumor cells (PTCs) to chemotherapeutic drugs. This study links fatty acid levels to polyamine accumulation, ultimately promoting EC progression and revealing the mechanism by which MS promotes EC progression. Targeting HOXB9 or ODC1 is expected to be a potential therapeutic strategy to control patients with MS-related progressive, drug-resistant, or relapsed EC.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS13106 | MetaboLights | 2025-11-08

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13106_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13106_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13106_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13106_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Polyamines are aliphatic polycations that have emerged as important determinants of cell growth and viability in rapidly proliferating cells, including in the pathogenic protozoan parasite Leishmania donovani. In L. donovani, the polyamine spermidine is synthesized by the successive conversion of ornithine into putrescine (catalyzed by ornithine decarboxylase or ODC) and putrescine into spermidine (catalyzed by spermidine synthase or SPDSYN). Deletion of either ODC (del-odc) or SPDSYN (del-spdsyn) from the L. donovani genome renders these parasites auxotrophic for polyamines and these mutants are impaired in their ability to survive both in culture and within the mammalian host without the addition of exogenous polyamine supplementation. Significantly, del-odc parasites immediately cease proliferation after putrescine is removed from the culture media and perish within two weeks, while spermidine starved del-spdsyn mutants, which retain intracellular putrescine pools, show a slow-growth phenotype, and persist for several weeks in culture. To elucidate the key differences within the proteome of putrescine-starved del-odc cells and spermidine-starved del-spdsyn parasites, a shotgun quantitative proteomics approach was undertaken using TMT labeling and LC-MS/MS analysis. Briefly, three biological replicates each for mid-log phase del-odc and del-spdsyn promastigotes grown in the presence of exogenous putrescine (for del-odc) or spermidine (for del-spdsyn) supplementation were washed to remove the exogenous polyamine supplementation and incubated in polyamine-free media. At 24 and 48 h, cells from each biological replicate were isolated and prepared for tandem mass tag (TMT) labeling and downstream LC-MS/MS analyses. Peptides were identified using a database generated from the reference genome of L. donovani BPK282A1 strain. Changes in relative protein abundance for the polyamine-starved del-odc and del-spdsyn cell lines at 24 and 48 h were calculated by comparing aggregate total reporter ion intensities for each protein to that of the corresponding polyamine-supplemented 0-h timepoint.

Project description:Non-small cell lung cancer (NSCLC) is the most lethal and prevalent type of lung cancer. In almost all types of cancer, the levels of polyamines (putrescine, spermidine, and spermine) are increased, playing a pivotal role in tumor proliferation. Indomethacin, a non-steroidal anti-inflammatory drug, increases the abundance of an enzyme termed spermidine/spermine-N1-acetyltransferase (SSAT) encoded by the SAT1 gene. This enzyme is a key player in the export of polyamines from the cell. The aim of this study was to compare the effect of indomethacin on two NSCLC cell lines, and their combinatory potential with polyamine-inhibitor drugs in NSCLC cell lines. A549 and H1299 NSCLC cells were exposed to indomethacin and evaluations included SAT1 expression, SSAT levels, and the metabolic status of cells. Moreover, the difference in polyamine synthesis enzymes among these cell lines as well as the synergistic effect of indomethacin and chemical inhibitors of the polyamine pathway enzymes on cell viability were investigated. Indomethacin increased the expression of SAT1 and levels of SSAT in both cell lines. In A549 cells, it significantly reduced the levels of putrescine and spermidine. However, in H1299 cells, the impact of treatment on the polyamine pathway was insignificant. Also, the metabolic features upstream of the polyamine pathway (i.e., ornithine and methionine) were increased. In A549 cells, the increase of ornithine correlated with the increase of several metabolites involved in the urea cycle. Evaluation of the levels of the polyamine synthesis enzymes showed that ornithine decarboxylase is increased in A549 cells, whereas S-adenosylmethionine-decarboxylase and polyamine oxidase are increased in H1299 cells. This observation correlated with relative resistance to polyamine synthesis inhibitors eflornithine and SAM486 (inhibitors of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, respectively), and MDL72527 (inhibitor of polyamine oxidase and spermine oxidase). Finally, indomethacin demonstrated a synergistic effect with MDL72527 in A549 cells and SAM486 in H1299 cells. Collectively, these results indicate that indomethacin alters polyamine metabolism in NSCLC cells and enhances the effect of polyamine synthesis inhibitors, such as MDL72527 or SAM486. However, this effect varies depending on the basal metabolic fingerprint of each type of cancer cell.

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OA-HOXB9-ODC1-Polyamine Axis Mediates Metabolic Syndrome Promoting Endometrial Cancer Progression

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