Blockade of the Short Form of Prolactin Receptor Induces FOXO3a/EIF-4EBP1–Mediated Cell Death in Uterine Cancer

Abstract

◥Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTEN wt and PTEN mut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G 0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1-mediated cell death in both PTEN wt and PTEN mut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.

6-Shogaol increase FOXO3a/Bim axis to inhibit ovarian cancer through ER stress/NF-κB

“…[11,19,36,37]. Over expression of FOXO3a could inhibit the growth and proliferation of cancer cells [38]. Bim is an activator BH3-only protein that binds to the mitochondrial membrane and increases its affinity for BAX and BAK, thereby releasing apoptotic factors such as cytochrome c and inducing apoptosis of tumor cells [39].…”

Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review)

“…PRL misregulation is also associated with glioma, uterine, prostate, renal cell, and pituitary tumors. In uterine cancer, blocking PRLR induces FOXO3a/EIF-4EBP1-mediated cell death (70). In glioma, the therapeutic block of PRLR enhances the response of tumor cells to chemotherapy (71).…”

Cytoplasmic eIF6 promotes OSCC malignant behavior through AKT pathway

“…M 6 A-modified (N 6 -Methyladenosine) eIF3C can be combined with YTHDF1 to accelerate the process of overall mRNA translation, thereby promoting tumorigenesis and metastasis[ 17 ]. In addition, the FOXO3a (forkhead box O3A) /eIF4EBP1 (eIF4E binding protein 1) axis plays a critical role in the inhibitory effect of G129R(a prolactin antagonist) on cell proliferation and cell cycle in uterine cancer[ 18 ]. In terms of tumor drug resistance, overexpression of eIF3a might play a guiding role in the application of platinum-based chemotherapy[ 19 ].…”