VERU-111 suppresses tumor growth and metastatic phenotypes of cervical cancer cells through the activation of p53 signaling pathway.
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ABSTRACT:
SUBMITTER: Kashyap VK
PROVIDER: S-EPMC8059100 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), ?-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3?. In molecular docking analysis, ormeloxifene showed proficient docking with ?-catenin and GSK3?. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0-G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 ?g/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving ?-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267-80. ©2017 AACR.
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Project description:The 14-3-3 sigma (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3 sigma was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3 sigma has not yet been characterized. Here, we studied the link between 14-3-3 sigma activities and p53 regulation. We found that 14-3-3 sigma interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3 sigma expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3 sigma antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3 sigma facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3 sigma appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3 sigma inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3 sigma system. These results defined an important p53 regulatory loop and suggested that 14-3-3 sigma expression can be considered for therapeutic intervention in cancers.
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Project description:Cervical cancer is known as the possible outcome of genital infection, while the molecular mechanisms of initiation, development, and metastasis of cervical cancer have not yet been fully elucidated. Our study aims to investigate the effects of microRNA-92a (miR-92a) on tumor growth and immune function by targeting PTEN via the MAPK/ERK signaling pathway in tumor-bearing mice. C57BL/6 female mice were used for tumor-bearing mouse models and their tumor and adjacent normal tissues were collected, and normal cervical tissues were obtained from normal mice. Serum levels of tumor necrosis factor-α (TNF-α) and soluble interleukin-2 receptor (sIL-2R) were detected by ELISA. The cells were divided into the normal, blank, negative control (NC), miR-92a mimic, miR-92a inhibitor, siRNA-PTEN, and miR-92a inhibitor + siRNA-PTEN groups. Dual-luciferase reporter assay was adopted to determine the relationship between PTEN and miR-92a. Expressions of miR-92a, PTEN, TNF-α, sIL-2R, ERK1, and ERK2 were tested by RT-qPCR and Western blotting. Cell proliferation was detected by cell count kit-8 (CCK-8); cell cycle and apoptosis were detected by flow cytometry. Compared with the normal cervical tissues and adjacent normal tissues, the cervical cancer tissues exhibited increased expressions of miR-92a, p-ERK1/2, and serum levels of TNF-α and sIL-2R while decreased PTEN expression. PTEN was confirmed to be the target gene of miR-92a. As compared with the blank and NC groups, expressions of miR-92a, ERK1 and ERK2 increased, and expressions of PTEN decreased in the miR-92a mimic group. The miR-92a mimic group exhibited increased expression levels of TNF-α and sIL-2R, cell proliferation, and cell number in S phase but decreased cell apoptosis, and cell number in G0/G1 phase, while the miR-92a inhibitor group followed opposite trends. miR-92a promotes tumor growth and suppresses immune function by inhibiting PTEN via activation of the MAPK/ERK signaling pathway in mice bearing U14 cervical cancer.
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Project description:Accumulated evidence suggests that glioma stem cells (GSCs) may contribute to therapy resistance in high-grade glioma (HGG). Although recent studies have shown that the serine/threonine kinase maternal embryonic leucine-zipper kinase (MELK) is abundantly expressed in various cancers, the function and mechanism of MELK remain elusive. Here, we demonstrate that MELK depletion by shRNA diminishes the growth of GSC-derived mouse intracranial tumors in vivo, induces glial fibrillary acidic protein (+) glial differentiation of GSCs leading to decreased malignancy of the resulting tumors, and prolongs survival periods of tumor-bearing mice. Tissue microarray analysis with 91 HGG tumors demonstrates that the proportion of MELK (+) cells is a statistically significant indicator of postsurgical survival periods. Mechanistically, MELK is regulated by the c-Jun NH(2)-terminal kinase (JNK) signaling and forms a complex with the oncoprotein c-JUN in GSCs but not in normal progenitors. MELK silencing induces p53 expression, whereas p53 inhibition induces MELK expression, indicating that MELK and p53 expression are mutually exclusive. Additionally, MELK silencing-mediated GSC apoptosis is partially rescued by both pharmacological p53 inhibition and p53 gene silencing, indicating that MELK action in GSCs is p53 dependent. Furthermore, irradiation of GSCs markedly elevates MELK mRNA and protein expression both in vitro and in vivo. Clinically, recurrent HGG tumors following the failure of radiation and chemotherapy exhibit a statistically significant elevation of MELK protein compared with untreated newly diagnosed HGG tumors. Together, our data indicate that GSCs, but not normal cells, depend on JNK-driven MELK/c-JUN signaling to regulate their survival, maintain GSCs in an immature state, and facilitate tumor radioresistance in a p53-dependent manner.
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