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KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion
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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