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Salinomycin as a death switch: how gastric cancer cells choose their demise
Pasqualina Laurenziello1, Margherita Luongo1, Francesca Lospinoso Severini1
1IRCCS CROB Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy.
Abstract:
Gastric cancer (GC) remains a significant global health challenge due to the prevalence of multidrug resistance (MDR) that leads to therapy failure. MDR is driven by tumor heterogeneity and the presence of cancer stem cells (CSCs). Drug repurposing represents an innovative therapeutic strategy to overcome MDR. In this view, Salinomycin (Sal) has shown promising anticancer activity and selectivity against CSCs. Since its mechanisms in GC are not fully understood, we investigated its activity in a panel of four GC cell lines: SNU1, NCI-N87, AGS, and KATO-III. Our results demonstrate that Sal induces distinct forms of regulated cell death (RCD) in a cell line-specific manner. Sal treatment led to apoptosis in SNU1 and NCI-N87 cells, while it triggered ferroptosis in AGS and KATO-III cells. Autophagy was a common early event in all cell lines. Western blot analysis confirmed the activation of distinct signaling axes: mTOR/survivin/CASP-3/BAX in apoptotic cells and mTOR/survivin/SLC7A11/GPX4 in ferroptotic cells. Bioinformatics analysis revealed a unique 20-differentially expressed gene signature for ferroptosis-prone GC cells. Notably, Sal significantly reduced the proportion of CD44+ and CD133+ CSCs in the drug-resistant KATO-III and NCI-N87 cell lines. By selectively inducing either apoptosis or ferroptosis, Sal effectively overcomes MDR and targets the CSC population by reducing the capability to form spheroids and colonies. Moreover, our ferroptosis-related gene signature resulted useful to stratify GC patients and was found associated with better outcomes, highlighting the translational potential of Sal treatment. Indeed, it was effective to promote both apoptotic and ferroptotic RCD on patient-derived gastric cancer organoids. Notably, autophagy was a common RCD mechanism also in this preclinical model. Our findings suggest that Sal is a promising candidate for GC treatment, and understanding a tumor's specific molecular susceptibilities could enable the development of personalized therapeutic strategies.
Insights
Salinomycin (Sal) effectively targets gastric cancer (GC) by inducing apoptosis or ferroptosis, overcoming multidrug resistance (MDR) and reducing cancer stem cells (CSCs). This drug repurposing offers a promising strategy for personalized GC therapy.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Gastric cancer (GC) presents a significant global health challenge, largely due to multidrug resistance (MDR) and tumor heterogeneity, including cancer stem cells (CSCs).
- Drug repurposing is an emerging strategy to overcome MDR in cancer therapy.
- Salinomycin (Sal) has demonstrated anticancer potential and selectivity against CSCs, but its mechanisms in GC require further elucidation.
Purpose of the Study:
- To investigate the efficacy and mechanisms of Salinomycin (Sal) in a panel of gastric cancer (GC) cell lines.
- To determine the specific types of regulated cell death (RCD) induced by Sal in different GC cell lines.
- To evaluate Sal's impact on cancer stem cells (CSCs) and its potential for overcoming multidrug resistance (MDR) in GC.
Main Methods:
- Treatment of four GC cell lines (SNU1, NCI-N87, AGS, KATO-III) with Salinomycin (Sal).
- Analysis of regulated cell death (RCD) pathways including apoptosis, ferroptosis, and autophagy via Western blot.
- Assessment of cancer stem cell (CSC) populations (CD44+, CD133+) and spheroid/colony formation.
- Bioinformatics analysis to identify a gene signature for ferroptosis-prone GC cells.
- Validation in patient-derived gastric cancer organoids.
Main Results:
- Sal induced distinct RCDs: apoptosis in SNU1/NCI-N87 cells and ferroptosis in AGS/KATO-III cells, with autophagy as a common early event.
- Western blot confirmed activation of specific signaling pathways related to apoptosis (mTOR/survivin/CASP-3/BAX) and ferroptosis (mTOR/survivin/SLC7A11/GPX4).
- Sal significantly reduced CSC populations and spheroid/colony formation in drug-resistant cell lines, demonstrating MDR overcoming potential.
- A 20-gene signature for ferroptosis-prone GC cells was identified and associated with better patient outcomes.
- Sal demonstrated efficacy in patient-derived gastric cancer organoids, inducing both apoptosis and ferroptosis.
Conclusions:
- Salinomycin (Sal) selectively induces apoptosis or ferroptosis in gastric cancer (GC) cells, effectively overcoming multidrug resistance (MDR) and targeting cancer stem cells (CSCs).
- The identified ferroptosis gene signature can aid in stratifying GC patients and predicting outcomes, suggesting personalized therapeutic strategies.
- Sal shows significant translational potential as a repurposed drug for GC treatment, with demonstrated efficacy in preclinical models including organoids.
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