Kinesin 12 (KIF15) contributes to the development and tumorigenicity of prostate cancer

Highlights

• Silencing of KIF15 inhibits proliferation and migration of PCa cell lines.

• KIF15 suppression significantly arrested cells at the G1 phase of the cell cycle.

• Downregulation of KIF15 resulted in altering the MEK-ERK pathway.

• KIF15 inhibition in human PCa xenograft models delayed tumor initiation and growth.

Abstract

In Asia, prostate cancer is becoming a growing concern, impacting both socially and economically, compared with what is seen in western countries. Hence, it is essential to know the mechanisms associated with the development and tumorigenesis of PCa for primary diagnosis, risk management, and development of therapy strategies against PCa. Kinesin family member 15 (KIF15), a kinesin family member, is a plus-end-directed kinesin that functions to form bipolar spindles. There is emerging evidence indicating that KIF15 plays a significant role in several malignancies, such as pancreatic cancer, hepatocellular carcinoma, lung adenocarcinoma, and breast cancer. Still, the function of KIF15 remains unclear in prostate cancer. Here, we study the functional importance of KIF15 in the tumorigenesis of PCa. The bioinformatic analysis from PCa patients revealed high KIF15 expression compared to normal prostate tissues. High expression hinting at a possible functional role of KIF15 in regulating cell proliferation of PCa, which was demonstrated by both in vitro and in vivo assays. Downregulation of KIF15 silenced the expression of CDK2, p-RB, and Cyclin D1 and likewise blocked the cells at the G1 stage of the cell cycle. In addition, KIF15 downregulation inhibited MEK-ERK signaling by significantly silencing p-ERK and p-MEK levels. In conclusion, this study confirmed the functional significance of KIF15 in the growth and development of prostate cancer and could be a novel therapeutic target for the treatment of PCa.

Introduction

According to the cancer statistics, Prostate Cancer (PCa) in the United States is considered one of the most diagnosed cancers and is the second leading reason for death in men. In 2020, around 33,330 PCa mortality occurred in the USA, and 191,930 new PCa development was diagnosed [1]. In Asia, prostate cancer is becoming a growing concern, impacting both socially and economically, comparable to what can be observed in western countries [2]. Furthermore, in organ-confined PCa, around 75% of patients fail surgical treatment and, within 10 years developed to a more aggressive or metastatic lethal disease [3]. Hence, it is necessary to identify the biological processes implicated in developing and tumorigenesis of PCa that may be useful for primary diagnosis and for the development of new therapeutic strategies. In addition, despite the notable growth in determining genomic variations in PCa, there is a need to identify novel genomic biomarkers and proteins [4].

Kinesins are essential biological motor proteins that assist the cell in the transport of various cellular cargos, including protein complexes, mRNAs, and membranous organelles at the expenditure of ATP [5]. The kinesin family member 15 (KIF15) is a plus-end-directed, N-terminal motor and a chromokinesin that functions to form bipolar spindles [6]. KIF15 plays an essential role in events, including neuronal development and processes such as proliferation, apoptosis, and differentiation [7]. Furthermore, there is an emerging indication that KIF15 plays a significant role in several malignancies, including pancreatic [8], hepatocellular [9], and breast carcinomas [10].

Drugs such as monastrol, terpendole E, S-trityl-L cysteine, and ispinesib have exhibited inhibitory potential against Kinesin 11 (Eg5). However, clinical trials have demonstrated that the cells develop resistance to these inhibitors through overexpressing KIF15 that replaces the function of Eg5. Therefore, KIF15 inhibitors will be of great value, and the development of inhibitors for KIF15 and its co-inhibition with Eg5 will be an excellent therapeutic approach [11,12]. Based on epigenetic and genetic variations, PCa development is a multistep process. Therefore, understanding the molecular pathways responsible for tumorigenesis, uncontrolled growth, and distant metastasis of PCa is needed to obtain a novel therapeutic strategy for this disease.

In this study, through in vitro and in vivo experiments, we attempted to study the functional importance of KIF15 in PCa. We used the information from The Cancer Genome Atlas (TCGA) database and analyzed the level of KIF15 expression in PCa patients. To detect cell proliferation, migration, and cell growth in WPMY1, Du145, and LNCap cells, we performed CCK8, wound healing assay, and colony formation assays and determined that KIF15 promotes proliferation through the MEK-ERK signaling pathway. In addition, PCa xenograft mouse models were established to validate the results of in vitro experiments. Briefly, we showed that KIF15 plays a crucial role in promoting PCa and might be a promising prognostic marker.