Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway.

The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Delta1-9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer

Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation.

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer

Assessment and Feedback Under Disruptive Circumstances in Trans-National Education

The COVID-19 pandemic outbreak and the lock-down and social distancing strategies adopted to contain it have drastically affected our daily lives and the routine businesses. Provision of educational services in a continuous and useful manner in such circumstances is a massive challenge and requires innovative methods. Effective assessment and feedback play a pivotal role in traditional teaching and learning approaches and it is of even more vital importance in disruptive conditions. This paper discusses different assessment and feedback techniques in the online delivery of higher education courses in lockdown scenarios. The effectiveness of these approaches is evaluated through qualitative and quantitative study of student and staff feedback for an engineering course being delivered as part of a transnational education (TNE) program. In the light of the results, recommendations are made to improve the assessment and feedback activities in disruptive circumstances

Sorafenib Sensitizes Solid Tumors to Apo2L/TRAIL and Apo2L/TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 Axis

<div><p>Background</p><p>Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (Apo22L/TRAIL). Previously, we showed that combining Apo2L/TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L/TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L/TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2. Monoclonal antibodies targeting either of these death receptors are being investigated as antitumor agents in clinical trials. We hypothesized that sorafenib and Apo2L/TRAIL or Apo2L/TRAIL death receptor agonist (TRA) antibodies against DR4 (mapatumumab) and DR5 (lexatumumab) will overcome resistance to Apo2L/TRAIL-mediated apoptosis and as increase antitumor efficacy in Apo2L/TRAIL-sensitive solid tumors.</p> <p>Methodology/Principal Findings</p><p>We found that Apo2L/TRAIL or TRA antibodies combined with sorafenib synergistically reduce cell growth and increase cell death across a panel of solid tumor cell lines in vitro. This panel included human breast, prostate, colon, liver and thyroid cancers. The cooperativity of these combinations was also observed <i>in</i><i>vivo</i>, as measured by tumor volume and TUNEL staining as a measure of apoptosis. We found that sorafenib inhibits Jak/Stat3 signaling and downregulates their target genes, including cyclin D1, cyclin D2 and Mcl-1, in a dose-dependent manner.</p> <p>Conclusions/Significance</p><p>The combination of sorafenib with Apo2L/TRAIL or Apo2L/TRAIL receptor agonist antibodies sensitizes Apo2L/TRAIL-resistant cells and increases the sensitivity of Apo2L/TRAIL-sensitive cells. Our findings demonstrate the involvement of the Jak2-Stat3-Mcl1 axis in response to sorafenib treatment, which may play a key role in sorafenib-mediated sensitization to Apo2L/TRAIL.</p> </div

Sorafenib, Apo2L/TRAIL, mapatumumab and lexatumumab are effective in delaying tumor growth <i>in vivo</i>.

<p>A-D. Effects of combinatorial therapy on DU145 (A), MDA-MB-231 (B), HepG2(C) and RKO (D) xenografts in nu/nu mice (n=3-7 mice/group). In A, B and D tumor growth was monitored by caliper measurements while in C by bioluminescence imaging (C). Statistical significance was performed using an unpaired, two-tailed Student’s t-test comparing the control with the treated mice at the end point (*p<0.05, **p<0.005). Mice were monitored for signs of overt toxicity and weight loss. E. Tissue from mice was harvested at 48 h after treatment and TUNEL assay performed.</p

Sorafenib in combination with Apo2L/TRAIL and TRA antibodies enhances cell death of solid tumors <i>in vitro</i>.

<p>A. Panel of prostate, breast, colon and thyroid cancer cell lines was treated with different concentrations of these drugs in combination with sorafenib for 24 hr and growth analyzed by CellTiter-Glo (n=3, mean+S.D). B 8505C thyroid cancer cells were treated with varying concentrations of sorafenib (1, 10 µM), Apo2L/TRAIL (25, 100 ng/mL), mapatumumab (100, 1000 ng/mL) or lexatumumab (100, 1000 ng/mL). C. A panel of cell lines was harvested and lysates prepared for Western blot analysis for total Stat3 and Jak2 levels.</p

Sorafenib sensitizes human HCC cell lines to cell death induced by Apo2L/TRAIL and TRA antibodies.

<p>A. HepG2, Hep3B and SNU449 cells were treated with sorafenib (4, 8, 12, 16 µM), Apo2L/TRAIL (25 ng/mL), mapatumumab (125, 250 and 1000 ng/mL) or lexatumumab for (125, 250 and 1000 ng/mL) for 24 h and cell viability was determined by CellTiter-Glo assay (n=3, mean+S.D.). B-D. HepG2, Hep3B and SNU449 cells were treated with varying concentrations of sorafenib in combination with Apo2L/TRAIL, mapatumumab or lexatumumab for 24 h and sub-G1 content was analyzed (C=Control, S=Sorafenib, T =TRAIL, M=Mapatumumab, L=Lexatumumab)..</p