PBK, targeted by EVI1, promotes metastasis and confers cisplatin resistance through inducing autophagy in high-grade serous ovarian carcinoma

Hanlin Ma,Shi Yan,Min Gao,Beihua Kong,Gonghua Qi,Yingwei Li,Ning Yang,Rongrong Li,Cunzhong Yuan,Huan Wu,Xiangxiang Wang

doi:10.1038/s41419-019-1415-6

Hanlin Ma, Shi Yan + Show 9 more

Open Access

https://doi.org/10.1038/s41419-019-1415-6

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Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most lethal type of gynecologic malignancy. Chemoresistance is the main reason for the poor prognosis of HGSOC. PDZ-binding kinase (PBK) promotes the malignant progression of various carcinomas. However, the roles and clinical significance of PBK in HGSOC remain unclear. Here, we reported that PBK was overexpressed in HGSOC tissues and cell lines. High PBK expression was associated with a poor prognosis, metastasis, and cisplatin resistance of HGSOC. Overexpression of PBK promoted autophagy and enhanced cisplatin resistance via the ERK/mTOR signaling pathway. Further study showed that inhibition of autophagy by chloroquine or bafilomycin A1 reversed PBK-induced cisplatin resistance. Overexpression of PBK decreased ovarian cancer responsiveness to cisplatin treatment through inducing autophagy in vivo. We also demonstrated that the PBK inhibitor OTS514 augmented the growth inhibition effect of cisplatin in vitro and in vivo. Moreover, ecotropic viral integration site-1 (EVI1) could regulate PBK expression through directly targeting the PBK promoter region. In conclusion, high PBK expression was correlated with a poor prognosis, metastasis, and cisplatin resistance through promoting autophagy in HGSOC. PBK might be a promising target for the early diagnosis and individual treatment of ovarian cancer.

Highlights

Ovarian cancer is the most lethal type of gynecologic malignancy[1]
The results showed that the MAPK, Rap[1], PI3K–AKT, and Hippo signaling pathways were strongly enriched in the PDZ-binding kinase (PBK) knockdown group (Supplementary Fig. S5B–C). Quantitative real-time PCR (qPCR) was performed to verify the downregulation of representative differentially expressed genes (DEGs) involved in the MAPK, Rap[1], and PI3K–AKT signaling pathways (Supplementary Fig. S5D)
PBK promotes autophagy through the ERK/mammalian target of rapamycin (mTOR) axis Considering that PBK was involved in the regulation of the MAPK and PI3K–AKT signaling pathway, which mediates the progression of autophagy, we investigated the role of PBK in the autophagy of ovarian cancer cells

Summary

Introduction

Ovarian cancer is the most lethal type of gynecologic malignancy[1]. In 2018, 22,240 new ovarian cancer cases and 14,070 ovarian cancer deaths are estimated to occur in the United States according to the American Cancer Society[2]. Ovarian cancer is conventionally treated with surgery and platinum/paclitaxel-based chemotherapy. High-grade serous ovarian carcinoma (HGSOC), the most common histological subtype, accounts for ~70% of all PDZ-binding kinase (PBK), known as T-LAK (lymphokine-activated killer T) cell-originated protein kinase (TOPK), was first cloned from the T-LAK cell subtraction cDNA fragment library[5]. PBK is a serine/ threonine kinase belonging to the mitogen-activated protein kinase kinase (MAPKK) family[6]. PBK is rarely expressed in normal tissues except for fetal and germ cells

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