title: YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.
abstract: Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ciamporcero
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yu Ku
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chintala
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Adelaiye
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ullio
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pizzimenti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Daga
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Azabdaftari
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Attwood
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barrera
authors.affiliation: Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pili
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human