Cellular signalling · 2026
Targeting the HIF-1α-BSG metabolic circuit reverses enzalutamide resistance in prostate cancer.
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Guo Xiuchen, Huang Jiacheng, Chen Zhiwei, Liao Haihong, Xu Yulin, Yu Yongjiang
Аннотация
BACKGROUND: Enzalutamide resistance limits durable control of castration-resistant prostate cancer (CRPC), but the mechanisms coordinating metabolic adaptation, cellular plasticity, and residual androgen receptor (AR) signaling remain incompletely understood. We investigated whether BSG, encoding basigin/CD147, contributes to this resistant state.
METHODS: We integrated reanalysis of an androgen-responsive reporter-based CRISPR activation screen with bulk and single-cell transcriptomic datasets, clinical specimens, and outcome data. Reciprocal BSG loss- and gain-of-function experiments were performed in parental and enzalutamide-resistant LNCaP and C4-2 cells. Drug response, cellular plasticity, glycolytic activity, hypoxia/HIF1A perturbation, pathway-directed inhibition, and resistant xenografts were evaluated.
RESULTS: BSG-activating guides were enriched in unsorted and androgen-responsive, but not androgen-independent, enzalutamide-resistant populations. BSG was elevated in resistant models and high-Gleason-score tumors, and high expression was associated with shorter progression-free survival. Single-cell analysis identified a CRPC-enriched tumor-cell state with high BSG and SLC16A3 expression, increased glycolysis and hypoxia-related activity, enhanced developmental plasticity, and retained AR-target gene expression. BSG depletion increased enzalutamide responsiveness and suppressed proliferation, clonogenic survival, migration, invasion, sphere formation, and stemness and epithelial-mesenchymal transition programs in resistant cells, whereas BSG overexpression produced reciprocal effects in parental cells. BSG depletion reduced AR and PSA abundance in LNCaP EnzR cells. It also reduced extracellular acidification, lactate production, glucose uptake, and the abundance of HK2, LDHA, MCT1, and MCT4. Hypoxia or HIF1A overexpression increased BSG-associated metabolic and plasticity programs, whereas BSG depletion attenuated most HIF-1α-induced changes without materially reducing HIF-1α. In resistant xenografts, BSG depletion or PX-478 enhanced tumor suppression by enzalutamide.
CONCLUSIONS: BSG contributes to an AR-retaining, hypoxia-associated glycolytic and plastic state that supports enzalutamide resistance.
METHODS: We integrated reanalysis of an androgen-responsive reporter-based CRISPR activation screen with bulk and single-cell transcriptomic datasets, clinical specimens, and outcome data. Reciprocal BSG loss- and gain-of-function experiments were performed in parental and enzalutamide-resistant LNCaP and C4-2 cells. Drug response, cellular plasticity, glycolytic activity, hypoxia/HIF1A perturbation, pathway-directed inhibition, and resistant xenografts were evaluated.
RESULTS: BSG-activating guides were enriched in unsorted and androgen-responsive, but not androgen-independent, enzalutamide-resistant populations. BSG was elevated in resistant models and high-Gleason-score tumors, and high expression was associated with shorter progression-free survival. Single-cell analysis identified a CRPC-enriched tumor-cell state with high BSG and SLC16A3 expression, increased glycolysis and hypoxia-related activity, enhanced developmental plasticity, and retained AR-target gene expression. BSG depletion increased enzalutamide responsiveness and suppressed proliferation, clonogenic survival, migration, invasion, sphere formation, and stemness and epithelial-mesenchymal transition programs in resistant cells, whereas BSG overexpression produced reciprocal effects in parental cells. BSG depletion reduced AR and PSA abundance in LNCaP EnzR cells. It also reduced extracellular acidification, lactate production, glucose uptake, and the abundance of HK2, LDHA, MCT1, and MCT4. Hypoxia or HIF1A overexpression increased BSG-associated metabolic and plasticity programs, whereas BSG depletion attenuated most HIF-1α-induced changes without materially reducing HIF-1α. In resistant xenografts, BSG depletion or PX-478 enhanced tumor suppression by enzalutamide.
CONCLUSIONS: BSG contributes to an AR-retaining, hypoxia-associated glycolytic and plastic state that supports enzalutamide resistance.