降低EPS8的表現性可能減緩Enzalutamide抵抗性攝護腺癌的疾病進展

黃國倫¹、黃維倫^1、2、吳俊賢^1、2、謝佩坊³、林嘉祥^1、2

¹義大醫療財團法人義大醫院 泌尿科；

²義守大學 醫學系

³中華醫事科技大學 醫學檢驗生物技術學系

Knockdown of EPS8 expression may attenuate disease progression in enzalutamide-resistant prostate cancer

Allen, Guo-Lun Haung¹, Wei-Lun Huang^1,2 ,Chun-Hsien Wu^1,2, Pei-Fang Hsieh^1,3, Victor C. Lin^1,2

Department of Urology¹, E-Da Hospital, Kaohsiung, Taiwan;

School of Medicine, College of Medicine², I-Shou University, Kaohsiung, Taiwan

Department of Medical Laboratory Science and Biotechnology³, Chung‑Hua University of Medical Tech-nology, Tainan, Taiwan

Purpose: Androgen deprivation therapies are the main treatment options for prostate cancer. However, resistance and disease progression of prostate cancer are common in most patients receiving these treatments. Consequently, identifying new targetable pathways that can help overcome resistance to current treatments is necessary. One such potential targetable pathway is epidermal growth factor receptor pathway substrate 8 (Eps8). Eps8 is initially identified as a novel substrate of EGFR kinase. Eps8 overexpression promotes mitosis and enhances malignant metastasis by activating the EMT and EGFR-regulated downstream signaling pathways. Conversely, Eps8 knockdown inhibits the progression of these cancers. We here investigated Eps8 expression in enzalutamide-resistant prostate cancer cells and explored the impact of this expression on epithelial-to-mesenchymal transition (EMT) and tumor cell activity in prostate cancer.

Materials and Methods: The LNCaP cell line and enzalutamide-resistant LNCaP (LNCaP Enz-R) cell lines are used for the investigation. Eps8 overexpression is observed in the LNCaP Enz-R cells by RT-PCR and Western blotting. Effects of Eps8 overexpression and knockdown on EMT, cell proliferation and viability are assessed through cells tranfection with pCMV-Eps8. Association of Ras/p53/JAK/PI3K signaling pathway and regulation of EMT is evaluated with expression of E-cadherin and α-SMA. In vivo experiments are conducted by subcutaneously inoculating cells into NOD-SCID mice to assess effects of Eps8 on EMT.

Results: In our study, Eps8 expression is higher in LNCaP Enz-R cells than in LNCaP cells (Figure 1). Furthermore, Eps8 overexpression increases in cell proliferation, cell viability, and the levels of EMT in both LNCaP and LNCaP Enz-R cells (Figure 2, 3). Conversely, after Eps8 knockdown, cell proliferation, cell viability, and the levels of EMT decrease in both LNCaP and LNCaP Enz-R cells (Figure 4, 5). Suppression of Ras/p53/JAK/PI3K signaling reverses Eps8 overexpression induced upregulation of EMT (Figure 6). EPS8-overexpressing tumor cells exhibited downregulation of E-cadherin but upregulation of theα-SMA. By contrast, Eps8 downregulation resulted in E-cadherin upregulation and α-SMA downregulation (Figure 7).

Conclusions: Our study highlights the significance of Eps8 expression in prostate cancer progression and prostate cancer cell viability. Eps8 activation promotes EMT, which is linked to the aggressive behavior of cancer and its resistance to drugs. On silencing Eps8, a reduction in both EMT and cancer cell viability is observed. These findings indicate the significant role of Eps8 in prostate cancer progression and drug resistance. Thus, Eps8 may be a promising target for developing innovative treatments.