👤 Zivar Alishahi

Therapy resistance is the principal obstacle to achieving cures in cancer patients and its successful tackling requires a deep understanding of the resistance mediators. Increasing evidence indicates that tumor phosphatases are novel and druggable targets in translational oncology and their modulation may hinder tumor growth and motility and potentiate therapeutic sensitivity in various neoplasms via regulation of various signal transduction pathways. Dual-specificity phosphatases (DUSPs) are key players of cell growth, survival and death and have essential roles in tumor initiation, malignant progression and therapy resistance through regulation of the MAPK signaling pathway. In this review, different aspects of DUSPs are discussed. A comprehensive literature review was performed using various websites including PubMed. We provide mechanistic insights into the roles of well-known DUSPs in resistance to a wide range of cancer therapeutic approaches including chemotherapy, radiation and molecular targeted therapy in human malignancies. Moreover, we discuss the development of DUSP modulators, with a focus on DUSP1 and 6 inhibitors. Ultimately, the preclinical investigations of small molecule inhibitors of DUSP1 and 6 are outlined. Emerging evidence indicates that the DUSP family is aberrantly expressed in human malignancies and plays critical roles in determining sensitivity to a wide range of cancer therapeutic strategies through regulation of the MAPK signaling pathways. Consequently, targeting DUSPs and their downstream molecules can pave the way for more effective cancer therapies. Show less

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells. Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib. We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail. Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC. Show less