Translational oncology · 2026
L-type calcium channel-mediated lipid metabolic reprogramming in gastric adenocarcinoma progression.
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Cui Miaomiao, Cheng Shuqiang, Wen Xianhui, Yang Hanlin, Huang Yun, Pan Li, Wei Sixi, Huang Hai
Аннотация
BACKGROUND: l-type calcium channels (LTCCs) play an important role in tumorigenesis, but their expression profile, functional significance, and therapeutic potential in gastric adenocarcinoma (GAC) remain unclear. Concurrently, aberrant lipid metabolism is widely acknowledged as a key driver of GAC progression, but its upstream regulatory mechanisms have yet to be fully elucidated. This study was designed to explore the association between LTCCs and lipid metabolic reprogramming in GAC and to investigate its influence on GAC progression and clinical outcomes.
METHODS: The expression profiles of LTCCs family members in GAC were analyzed using the TCGA database. Gastric cancer cells were treated with the LTCCs antagonist (+)-Bay-K-8644, and its effect on the malignant phenotype of the cells was detected by CCK-8, clone formation, scratch healing and transwell assay. Metabolic changes were analyzed by UPLC-Q-TOF-MS metabolomics. The role of lipid metabolism in the regulation of LTCCs was verified by palmitic acid (PA) backfill assay.
RESULTS: Bioinformatics analysis showed that Voltage-dependent LTCCs subunit alpha-1D (CACNA1D) was up-regulated in GAC. CACNA1D had excellent diagnostic value and its high expression was associated with poor prognosis. (+)-Bay-K-8644 significantly inhibited gastric cancer cells' proliferation, clone formation, and migration ability. Metabolomics analysis revealed that (+)-Bay-K-8644 treatment resulted in reprogramming of lipid metabolism. Exogenous PA was able to partially reverse the anticancer effects of (+)-Bay-K-8644 and restore cell proliferation and migration.
CONCLUSIONS: This study elucidated the unique expression pattern of LTCCs in GAC for the first time, and confirmed that LTCCs antagonism exerts anticancer effects by inducing reprogramming of lipid metabolism. These findings provide a theoretical basis for repositioning calcium channel blockers for GAC therapy and suggest that combined targeting of calcium channels and lipid metabolism may become a new strategy for GAC treatment.
METHODS: The expression profiles of LTCCs family members in GAC were analyzed using the TCGA database. Gastric cancer cells were treated with the LTCCs antagonist (+)-Bay-K-8644, and its effect on the malignant phenotype of the cells was detected by CCK-8, clone formation, scratch healing and transwell assay. Metabolic changes were analyzed by UPLC-Q-TOF-MS metabolomics. The role of lipid metabolism in the regulation of LTCCs was verified by palmitic acid (PA) backfill assay.
RESULTS: Bioinformatics analysis showed that Voltage-dependent LTCCs subunit alpha-1D (CACNA1D) was up-regulated in GAC. CACNA1D had excellent diagnostic value and its high expression was associated with poor prognosis. (+)-Bay-K-8644 significantly inhibited gastric cancer cells' proliferation, clone formation, and migration ability. Metabolomics analysis revealed that (+)-Bay-K-8644 treatment resulted in reprogramming of lipid metabolism. Exogenous PA was able to partially reverse the anticancer effects of (+)-Bay-K-8644 and restore cell proliferation and migration.
CONCLUSIONS: This study elucidated the unique expression pattern of LTCCs in GAC for the first time, and confirmed that LTCCs antagonism exerts anticancer effects by inducing reprogramming of lipid metabolism. These findings provide a theoretical basis for repositioning calcium channel blockers for GAC therapy and suggest that combined targeting of calcium channels and lipid metabolism may become a new strategy for GAC treatment.