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EPS8 Differentially Regulates Antioxidant Defense and Mitochondrial Homeostatic Signaling in LNCaP and Enzalutamide-resistant LNCaP Cells.

Sih-Han Chen·Chun-Hsien Wu·Pei-Fang Hsieh·Wen-Chi Huang·Yu-Lin Yang·Victor C Lin·Ming-Wei Lin
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Abstract

BACKGROUND/AIM: Epidermal growth factor receptor pathway substrate 8 (EPS8) is an adaptor protein implicated in tumor progression and therapeutic resistance; however, its role in mitochondrial homeostatic signaling and antioxidant regulation remains unclear. This study examined the effects of EPS8 modulation in lymph node carcinoma of the prostate (LNCaP) and enzalutamide-resistant LNCaP (LNCaP-Enz) cells. MATERIALS AND METHODS: LNCaP-Enz cells were generated by long-term exposure to enzalutamide and maintained in 5 μM enzalutamide. EPS8 expression was modulated by plasmid-mediated overexpression or shRNA-mediated knockdown. Superoxide dismutase (SOD) activity and cellular adenosine triphosphate (ATP) levels were measured using colorimetric assays. Mitochondrial membrane potential (ΔΨm) was evaluated using JC-1 fluorescence, and mitochondrial staining patterns were qualitatively examined using MitoTracker Green staining. Protein expression associated with antioxidant defense, mitochondrial dynamics, mitochondrial stress response, mitochondrial biogenesis, and AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling was analyzed by western blotting. RESULTS: EPS8 overexpression increased SOD activity and the expression of SOD1 and SOD2, whereas EPS8 knockdown reduced these antioxidant parameters. Conversely, EPS8 silencing increased cellular ATP levels and enhanced JC-1 red fluorescence patterns. EPS8 silencing increased MFN1 and OPA1 expression and reduced DRP1 expression, consistent with a fusion-associated mitochondrial profile. EPS8 silencing also increased SIRT1, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-mTOR/mTOR, but reduced HSP60, LONP1, ATF5, and CEBPβ expression. CONCLUSION: EPS8 differentially regulates SOD-associated antioxidant capacity and mitochondrial homeostatic signaling in LNCaP-based cell models. Further studies are required to determine whether EPS8 modulation affects enzalutamide responsiveness.

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HumansMalePhenylthiohydantoinDrug Resistance, NeoplasmBenzamidesMitochondriaSignal TransductionNitrilesAntioxidantsProstatic NeoplasmsAdaptor Proteins, Signal TransducingCell Line, TumorSuperoxide DismutaseMembrane Potential, MitochondrialHomeostasisAMPK–mTOR signalingEPS8LNCaPantioxidant defenseenzalutamide resistancemitochondrial homeostasisJournal Article

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BibTeXRIS

Sih-Han Chen, Chun-Hsien Wu, Pei-Fang Hsieh, Wen-Chi Huang, Yu-Lin Yang, Victor C Lin, Ming-Wei Lin. 2026. EPS8 Differentially Regulates Antioxidant Defense and Mitochondrial Homeostatic Signaling in LNCaP and Enzalutamide-resistant LNCaP Cells.. https://doi.org/10.21873/cgp.20611

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