Author ORCID Identifier

https://orcid.org/ 0000-0003-4811-2565

Date Available

12-1-2026

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Advisor

Dr. Qing-Bai She

Abstract

Dysregulation of polyamine metabolism has been linked to colorectal cancer (CRC) development. We recently reported that spermine synthase (SMS), a polyamine biosynthetic enzyme converting spermidine to spermine, is overexpressed in CRC. The overexpression of SMS is necessary to balance cellular spermidine levels, facilitating CRC tumorigenesis. Our findings suggest SMS as an attractive therapeutic target in CRC. However, genetic depletion of SMS expression only shows a modest antitumor effect. Through unbiased metabolomics and transcriptomics analyses, we identified reprogramming of lipid metabolism as among the most impacted metabolic changes by SMS depletion in CRC cells. Specifically, SMS inhibition significantly promotes phospholipid hydrolysis by upregulating phospholipase A2 group IIA (PLA2G2A) expression, leading to a marked increase in the levels of free long-chain fatty acids, especially polyunsaturated fatty acids (PUFAs), and their acylcarnitines to sustain fatty acid oxidation and mitochondrial respiration. Furthermore, we found that the FOXO3a transcriptional factor was activated by SMS depletion via spermidine-targeted inhibition of EP300-mediated acetylation of FOXO3a, leading to the transcriptional upregulation of PLA2G2A expression. Ferroptosis occurs due to the accumulation of oxidized PUFAs on membrane phospholipids and is triggered by failure of the glutathione-dependent lipid peroxide scavenging pathway (system xc-/GPX4). While given the established role of PUFAs in promoting ferroptosis, SMS inhibition-induced elevation of PUFAs only slightly increases lipid peroxidation in CRC cells. However, genetic depletion or pharmacological inhibition of SMS in combination with pharmacological inhibition of GPX4 or its upstream regulator system xc- synergistically induces lipid peroxidation, leading to ferroptosis induction and marked suppression of CRC cell growth in vitro and xenograft tumor growth in vivo. Notably, silencing of either FOXO3a or PLA2G2A expression in SMS-depleted CRC cells profoundly attenuates lipid peroxidation induced by the blockade of the lipid peroxide scavenging pathway. Collectively, these results reveal that the FOXO3a/PLA2G2A signaling axis mediates SMS inhibition-induced lipid metabolism reprogramming to sustain mitochondrial respiration and cell survival, thereby maintaining CRC tumorigenesis while creating vulnerability that can be therapeutically targeted by induction of ferroptosis. Thus, co-targeting SMS and system xc-/GPX4 is a potentially promising therapeutic strategy for treating SMS-overexpressing CRCs.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.398

Funding Information

This study was supported by the National Cancer Institute T32 Training Grant (T32 CA 165990) in 2022 to 2024.

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Available for download on Tuesday, December 01, 2026

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