p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

Abstract

Abstractp38 kinases activated by growth factors, hormones, and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology. Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer, although the mechanistic basis for this association is poorly understood. In this study, we report that p38 activation in cervical cancer cells is driven by osteopontin (OPN), an extracellular matrix-associated cytokine that drives invasive progression. OPN regulates CD44-mediated p38 phosphorylation that induces NF-kB activation and NF-kB-dependent expression of furin, an extracellular protease implicated in human papilloma virus (HPV) processing that enhances cervical cancer cell motility. OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells. OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6, p38a/b or NF-kB signaling. In a mouse xenograft model of human cervical cancer, tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA (shRNA)-mediated OPN silencing. Furin overexpression similarly augmented tumor growth in the model, whereas blocking MKK3/6, p38, or furin reduced OPN-induced cervical tumor growth. Analysis of clinical specimens revealed that enhanced expression of OPN, phosphorylated NF-kB, p65, and furin correlated with cervical cancer progression, further strengthening the in vitro and in vivo results. In summary, our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer.

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

“…15,33 Both in our and other studies, osteopontin effects were delivered during late-stage metastasis, since similar results were obtained from s.c. and i.v. models.…”

“…models. 15,33 Hence, the cytokine is likely dispensable for tumor dissemination from the primary site, but is required for circulating tumor cell engraftment in the lungs. Since circulating tumor cells are ubiquitous in cancer patients with minimal disease and most cancer patients will already have metastasis at the time of diagnosis, 4,5 mediators of end-organ colonization such as osteopontin are marked targets for therapy.…”

Osteopontin Knockdown Inhibits av,�3Integrin-Induced Cell Migration and Invasion and Promotes Apoptosis of Breast Cancer Cells by Inducing Autophagy and Inactivating the PI3K/Akt/mTOR Pathway

“…OPN has been shown to be strongly associated with tumor progression [7,9,11,][36] and has been shown to cause metastasis in a rat breast cancer model [37]. In addition, high circulating levels of OPN have been reported in patients with metastatic breast cancer [27].…”

“…OPN plays important physiological roles in bone remodeling [3], the immune response [4] and inflammation [5]. OPN is also well-known as a tumor-associated protein, and elevated OPN has been detected in a wide range of human tumors, such as breast [6,7], prostate [8,9], liver [10], cervical [11] and lung cancers [12,13]. Overexpression of OPN has also been detected in tumor cells and tumor-infiltrating inflammatory cells in breast cancer [14], and elevated serum levels of OPN in breast carcinoma have been associated with reduced survival [15].…”

β-elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor β and induces sensitization to cisplatin

“…MKK3 and MKK6 are two kinases that act upstream of p38 MApK. After activation by MKK kinases such as tAK1, AsK1 and MlKs (21,22), MKK3/6 can affect the activity of MsK1, Il-12, nF-κB, Mcl-1 and p53 by the phosphorylation of p38 MApK (34)(35)(36)(37)(38). MKK3/6-p38 activation negatively regulates proliferation via attenuation of the promoter activity of cyclin D1, increasing the percentage of cells in g0/g1 phase of the cell cycle, while MKK1-erK1/2 activation has the opposite effect (39).…”