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

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.

Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer

“…Since we previously reported that the autophagic pathway was altered in response to acute iron overload conditions in gynecological cells 30 and that EVI1 expression may regulate the expression of PDZ-binding kinase which leads to increased autophagy to confer chemoresistance 58 , we next investigated whether chronic iron exposure may also alter the autophagic pathway. We identified a subtle reduction in both LC3B-I and LC3B-II (the nonconjugated and conjugated forms, respectively) protein without a clear notable change in p62/sequestosome protein (Fig.…”

ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2

“…However, some studies found that autophagy inhibits the malignant biological behavior of tumors [15, 16]. PBK promotes the metastasis of serous ovarian carcinoma and confers cisplatin resistance [17]. OGT was downregulated in ovarian cancer, which in turn, promotes cisplatin resistance by inducing autophagy [18].…”

EVI1 as a Marker for Lymph Node Metastasis in HNSCC

“…This might explain why a high EVI1 expression indicates a poor survival in several tumor types and not in HNSCC. For example, in colon and ovarian cancer, EVI1 is associated with a higher metastasis rate [31,33]. A formation of several subgroups by p16 status and place of origin might show that in one or the other subgroup, a high EVI1 expression is associated with a poor prognosis.…”