KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

Lin Gao,Bo Han,Weiwen Chen,Meng Wang,Hanchen Dong,Qianni Li,Tingting Feng,Wenjie Cai,Ru Zhao,Feifei Sun,Xueting Xiong,Wenbo Zhang,Yiming Qin,Qianshuo Yin,Jing Hu,Xueqing Chen,Junmei Liu,Hui Liu,Xin Wang

doi:10.3389/fonc.2021.679173

Abstract

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide [1]
Our previous study showed that Kinesin family member 15 (KIF15) promotes cell proliferation in androgen dependent cell line LNCaP and Castration-resistant prostate cancer (CRPC) cell lines, including C4-2B, 22Rv1, and PC3 [29], these results suggest that KIF15 may correlate with CRPC progression
Our studies reveal a novel role of KIF15 that promotes CRPC by activating epidermal growth factor receptor (EGFR) signaling pathway in both androgen receptor (AR)-positive and ARnegative cells

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide [1]. Androgen deprivation treatment is the standard treatment for patients with advanced PCa [2]. A more aggressive castration-resistant prostate cancer (CRPC) inevitably develops [3]. Several novel therapeutic agents have been developed for CRPC, but the prognosis for patients with CRPC remains poor [4, 5]. The identification of novel therapeutic targets for CRPC is an urgent issue.

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