The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC


Autoři: Matthew Brown aff001;  Wanbin Zhang aff002;  Deyue Yan aff002;  Rajath Kenath aff004;  Le Le aff004;  He Wang aff004;  Daniel Delitto aff005;  David Ostrov aff006;  Keith Robertson aff007;  Chen Liu aff004;  Kien Pham aff004
Působiště autorů: Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, United States of America aff001;  School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, P.R. China aff002;  Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, United States of America aff003;  Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America aff004;  Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America aff005;  Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America aff006;  Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America aff007;  Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America aff008
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226917

Souhrn

Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin’s action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

Klíčová slova:

Adenocarcinomas – Apoptosis – Cancer immunotherapy – Cancer treatment – Cell migration – Hyperexpression techniques – Chemotherapeutic agents – Pancreatic cancer


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