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Targeting USP8 with odoroside A regulates LXRβ-mediated fatty acid metabolic reprogramming against colorectal cancer
Yan-Yan Chen1,2, Fang-Fang Liu1, Shi-Yuan Wen3
1State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China.
Abstract:
Colorectal cancer (CRC) remains a significant global health challenge, characterized by high post-surgical recurrence and poor survival outcomes. This study explores the therapeutic potential of odoroside A (OA), a natural compound derived from Nerium oleander, focusing on its ability to modulate lipid metabolism and induce cancer cell death on CRC. In a subcutaneous xenograft tumor model with HT29 and RKO cells, OA achieved inhibition ratios of 81.07% and 78.26% at a dose of 1.5 mg/kg, respectively. Mechanistic insights revealed that OA induced lipid accumulation and triggered cell death through lipid peroxidation, primarily by inhibiting fatty acid oxidation (FAO) pathways. This effect was supported by decreased mitochondrial FAO activity and reduced expression of FAO-related proteins, including CPT1A, CPT1B, CPT1C, CPT2, and ACSL1. Additionally, OA targeted ubiquitin-specific peptidase 8 (USP8), promoting the ubiquitination and degradation of liver X receptor beta (LXRβ), a critical regulator of lipid metabolism. This downregulation of LXRβ further disrupted FAO. This study establishes a foundation for developing OA as a natural compound-based anticancer therapy for CRC and identifies a novel link between USP8 and LXRβ, offering new insights into lipid metabolism on CRC.
Insights
Odoroside A, a natural compound, effectively inhibits colorectal cancer (CRC) growth by disrupting lipid metabolism. It triggers cancer cell death through lipid peroxidation and targets key proteins involved in fatty acid oxidation.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Colorectal cancer (CRC) presents significant challenges due to high recurrence and poor survival rates.
- Targeting cancer cell metabolism offers a promising therapeutic avenue.
Purpose of the Study:
- To investigate the anticancer potential of odoroside A (OA), a natural compound from Nerium oleander, against colorectal cancer.
- To elucidate the mechanisms by which OA affects lipid metabolism and induces cancer cell death.
Main Methods:
- Utilized a subcutaneous xenograft tumor model with HT29 and RKO colorectal cancer cells.
- Assessed OA's effects on tumor growth, lipid metabolism, mitochondrial fatty acid oxidation (FAO), and protein expression.
- Investigated the interaction of OA with ubiquitin-specific peptidase 8 (USP8) and liver X receptor beta (LXRβ).
Main Results:
- OA demonstrated significant tumor inhibition ratios (81.07% for HT29, 78.26% for RKO) at 1.5 mg/kg.
- OA induced lipid accumulation and cell death via lipid peroxidation by inhibiting FAO pathways.
- OA decreased mitochondrial FAO activity and reduced expression of FAO-related proteins (CPT1A-C, CPT2, ACSL1).
- OA promoted USP8-mediated ubiquitination and degradation of LXRβ, further disrupting FAO.
Conclusions:
- Odoroside A shows therapeutic potential as a natural compound-based anticancer therapy for colorectal cancer.
- OA's mechanism involves inhibiting fatty acid oxidation and targeting the USP8-LXRβ pathway.
- This study reveals a novel link between USP8 and LXRβ in colorectal cancer lipid metabolism.
