Targeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis

Abstract

Background Prostate cancer (PCa) is considered one of the most prevalent malignancy globally, and metastasis is a major cause of death. Apigenin (API) is a dietary flavonoid which exerts an antimetastatic effect in various cancer types. Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a crucial modulator of tumor growth and metastasis in cancers. However, the role and underlying regulatory mechanisms of SPOCK1 in the API-mediated antimetastatic effects of PCa remain unclear. Methods MTS, colony formation, wound-healing, and transwell assays were conducted to evaluate the effects of API on PCa cell proliferative, migratory, and invasive potentials. In vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. PCa cells were transfected with either Snail-, Slug-, SPOCK1-overexpressing vector, or small hairpin (sh)SPOCK1 to determine the invasive abilities and expression levels of SPOCK1 and epithelial-to-mesenchymal transition (EMT) biomarkers in response to API treatment. Immunohistochemical (IHC) assays were carried out to evaluate the expression level of SPOCK1 in PCa xenografts and a PCa tissue array. Associations of SPOCK1 expression with clinicopathological features and prognoses of patients with PCa were analyzed by GEO or TCGA RNA-sequencing data. Results API significantly suppressed in vitro PCa cell proliferation, migration, and invasion and inhibited in vivo PCa tumor growth and metastasis. Moreover, survival times of animals were also prolonged after API treatment. Mechanistic studies revealed that API treatment resulted in downregulation of SPOCK1, which was accompanied by reduced expressions of mesenchymal markers and subsequent attenuation of invasive abilities of PCa cells. Overexpression of SPOCK1 in PCa xenografts resulted in significant promotion of tumor progression and relieved the anticancer activities induced by API, whereas knockdown of SPOCK1 had opposite effects. In clinical, SPOCK1 levels were higher in tumor tissues compared to non-tumor tissues, which was also significantly correlated with shorter disease-free survival in PCa patients. Conclusions Levels of SPOCK1 increase with the progression of human PCa which suggests that SPOCK1 may act as a prognostic marker or therapeutic target for patients with PCa. Suppression of SPOCK1-mediated EMT signaling contributes to the antiproliferative and antimetastatic activities of API in vitro and in vivo. Electronic supplementary material The online version of this article (10.1186/s13046-019-1247-3) contains supplementary material, which is available to authorized users.

Histone Demethylase JMJD1A Promotes Tumor Progression via Activating Snail in Prostate Cancer

“…Prostate cancer is one of the most commonly diagnosed malignancies and the second leading cause of cancer-related death in American men (1). Androgen deprivation therapy (ADT) remains the primary clinical treatment for patients in the early stage of prostate cancer (2). However, most prostate cancer tumors become resistant to ADT and progress to a lethal stage called castrationresistant prostate cancer (CRPC), which is characterized by aggressive growth and distal organ metastasis, and is incurable (3).…”

Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets

“…Numerous natural compounds have been shown to revert EMT in PCa cells and xenografts, particularly by modulating the PI3K/Akt and Wnt/β-catenin signaling cascades [216][217][218][219][220][221][222][223][224][225][226]. In addition, urokinase-type plasminogen activator (uPA)-, Y-box binding protein-1 (YB-1)-and SPARC/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1)-mediated suppression of EMT contributed to the anti-invasive activity of quercetin, fisetin, and apigenin, respectively [227][228][229].…”

Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer

“…The stained TMAs were viewed under an Olympus BX50 light microscope (Olympus, Tokyo, Japan), and images were captured by a SPOT digital microscope camera head. To determine the intensity of Naa10p expression, the staining results were scored under a light microscope as described previously 24 .…”