KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion
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Published on: March 15, 2024
Man Li1,2, Xuexin Yu2, Yuanji Liu2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510080, China.
Abstract:
Understanding the mechanisms underlying Kirsten rat sarcoma (KRAS) mutation-driven development and progression of pancreatic ductal adenocarcinoma (PDAC) may facilitate the discovery of novel strategies for KRAS-mutant PDAC (KRASmut-PDAC) treatment. Here, it is reported that downregulation of arachidonate 15-lipoxygenase (ALOX15B) significantly correlated with poor outcomes in patients with KRASmut-PDAC. Mechanistically, KRASmut/ERK1-elicited phosphorylation of ABHD17C promotes depalmitoylation and membrane-to-cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10. Notably, treatment with methyl protodioscin (MPD), a steroid saponin primarily purified from polygonatum sibiricum rhizome, restored the S-palmitoylation and membrane location of ALOX15B via disruption of the ABHD17C/ALOX15B interaction, consequently resulting in significant inhibition of growth rate of patient-derived KRASmut-PDAC organoids in vitro and KRASmut-PDAC-formed tumor in vivo via induction of ferroptosis. Therefore, these findings unveil a prominent role of ferroptosis evasion in KRASmut-PDAC progression and highlight the potential of targeting KRAS/ERK1/ABHD17C/ALOX15B axis in KRASmut-PDAC treatment.
Insights
Downregulation of ALOX15B worsens outcomes in KRAS-mutant pancreatic cancer. Methyl protodioscin restores ALOX15B, inhibiting tumor growth by inducing ferroptosis, offering a new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Kirsten rat sarcoma (KRAS) mutations drive pancreatic ductal adenocarcinoma (PDAC) progression.
- Understanding KRAS-mutant PDAC (KRASmut-PDAC) mechanisms is crucial for developing new treatments.
- Arachidonate 15-lipoxygenase (ALOX15B) downregulation is linked to poor outcomes in KRASmut-PDAC.
Purpose of the Study:
- To elucidate the role of ALOX15B in KRASmut-PDAC progression.
- To investigate the molecular mechanisms by which ALOX15B is regulated in KRASmut-PDAC.
- To evaluate the therapeutic potential of targeting the KRAS/ERK1/ABHD17C/ALOX15B axis.
Main Methods:
- Analysis of patient outcomes correlated with ALOX15B levels.
- Investigation of KRASmut/ERK1-mediated phosphorylation of ABHD17C.
- Assessment of ALOX15B depalmitoylation, translocation, and degradation.
- In vitro and in vivo studies using methyl protodioscin (MPD) on KRASmut-PDAC organoids and tumors.
- Evaluation of ferroptosis induction as a mechanism of action.
Main Results:
- Downregulation of ALOX15B significantly correlated with poor prognosis in KRASmut-PDAC patients.
- KRASmut/ERK1 signaling promotes ALOX15B degradation via ABHD17C-mediated depalmitoylation and proteasomal pathways.
- MPD treatment restored ALOX15B S-palmitoylation and membrane localization by disrupting the ABHD17C/ALOX15B interaction.
- MPD treatment significantly inhibited KRASmut-PDAC growth in vitro and in vivo by inducing ferroptosis.
Conclusions:
- Ferroptosis evasion is a key mechanism in KRASmut-PDAC progression.
- Targeting the KRAS/ERK1/ABHD17C/ALOX15B axis represents a promising therapeutic strategy for KRASmut-PDAC.
- MPD demonstrates potential as a novel therapeutic agent for KRASmut-PDAC by reactivating ALOX15B-mediated ferroptosis.
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