2. Academic Validation
  3. SCAMP3 and EPS8 Cooperatively Regulate EGFR Signaling to Promote Enzalutamide Resistance and Metastatic Potential in Prostate Cancer

SCAMP3 and EPS8 Cooperatively Regulate EGFR Signaling to Promote Enzalutamide Resistance and Metastatic Potential in Prostate Cancer

  • Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):953-970. doi: 10.21873/cgp.20549.
Wei-Lun Huang # 1 2 3,  Pei-Fang Hsieh # 1 4,  Sih-Han Chen 1 2 3,  Richard Chen-Yu Wu 1 2 3 5,  Hsing-Cha Mai 1 2,  Chun-Hsien Wu 1 2,  See-Tong Pang 6 7,  Yu-Lin Yang 4 8,  Victor Chia-Hsiang Lin 9 2
Affiliations

Affiliations

  • 1 Division of Urology, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan, R.O.C.
  • 2 Department of Nursing, I-Shou University, Kaohsiung, Taiwan, R.O.C.
  • 3 School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C.
  • 4 Department of Medical Laboratory Science and Biotechnology, Chung-Hua University of Medical Technology, Tainan, Taiwan, R.O.C.
  • 5 Department of Information Engineering, I-Shou University, Kaohsiung, Taiwan, R.O.C.
  • 6 Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan, R.O.C.
  • 7 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan, R.O.C.
  • 8 Graduate Institute of Biological Science and Technology, Chung-Hwa College of Medical Technology, Tainan, Taiwan, R.O.C.
  • 9 Division of Urology, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan, R.O.C.; [email protected] [email protected].
  • # Contributed equally.
PMID: 41151858 DOI: 10.21873/cgp.20549
Abstract

Background/aim: Prostate Cancer is the second most common malignancy among men worldwide, with progression to castration-resistant prostate Cancer (CRPC) posing significant therapeutic challenges. Enzalutamide, a second-generation Androgen Receptor antagonist, initially demonstrates efficacy in treating metastatic CRPC; however, resistance inevitably develops. Dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway has been implicated in therapy resistance and metastatic progression. Secretory carrier membrane protein 3 (SCAMP3) and epidermal growth factor receptor substrate 8 (EPS8) are known regulators of EGFR trafficking and signaling. This study aimed to investigate their cooperative roles in enzalutamide-resistant prostate Cancer cells.

Materials and methods: LNCap prostate Cancer cells and their enzalutamide-resistant derivatives (LNCap-Enz) were treated with 100 ng/ml epidermal growth factor (EGF). Protein expression and interactions were analyzed by Western blotting and co-immunoprecipitation. SCAMP3 and EPS8 were knocked down using shRNA technology, while complementary overexpression studies were conducted using pcDNA-SCAMP3 and pcDNA-EPS8 vectors. Effects on EGF receptor (EGFR) expression and downstream signaling molecules (STAT3, Akt, ERK) were evaluated in both loss-of-function and gain-of-function models.

Results: EGF stimulation enhanced the expression of EGFR, SCAMP3, and EPS8 in both LNCap and LNCap-Enz cells while promoting formation of a protein complex involving these proteins and the Androgen Receptor (AR-V7). Knockdown of SCAMP3 or EPS8 reduced EGFR expression and attenuated STAT3, Akt, and ERK activation. Conversely, overexpression of SCAMP3 or EPS8 increased EGFR levels and enhanced downstream signaling activation. These bidirectional effects highlight the functional interdependence between SCAMP3 and EPS8 in regulating EGFR stability and signaling.

Conclusion: SCAMP3 and EPS8 cooperatively maintain EGFR stability and signaling in prostate Cancer cells, playing a critical role in enzalutamide resistance and metastatic progression. Targeting the SCAMP3-EPS8-EGFR axis offers promising therapeutic opportunities for advanced prostate Cancer.

Keywords

EGFR signaling; EPS8; Prostate cancer; SCAMP3; drug resistance; enzalutamide resistance; metastasis.

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