YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

E. Ciamporcero, H. Shen, S. Ramakrishnan, S. Yu Ku, S. Chintala, L. Shen, R. Adelaiye, K. M. Miles, C. Ullio, S. Pizzimenti, M. Daga, G. Azabdaftari, K. Attwood, C. Johnson, J. Zhang, G. Barrera, Roberto Pili

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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.

Original languageEnglish (US)
Pages (from-to)1541-1553
Number of pages13
JournalOncogene
Volume35
Issue number12
DOIs
StatePublished - Mar 24 2016

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DNA Damage
Carcinoma
Proteins
Cisplatin
Drug Therapy
Therapeutics
Pharmacology
Apoptosis
Neoplasms
Radiation Effects
Standard of Care
Platinum
Heterografts
Urinary Bladder Neoplasms
Non-Small Cell Lung Carcinoma
Ovarian Neoplasms
Cell Proliferation
Muscles
DNA

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ciamporcero, E., Shen, H., Ramakrishnan, S., Yu Ku, S., Chintala, S., Shen, L., ... Pili, R. (2016). YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. Oncogene, 35(12), 1541-1553. https://doi.org/10.1038/onc.2015.219

YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. / Ciamporcero, E.; Shen, H.; Ramakrishnan, S.; Yu Ku, S.; Chintala, S.; Shen, L.; Adelaiye, R.; Miles, K. M.; Ullio, C.; Pizzimenti, S.; Daga, M.; Azabdaftari, G.; Attwood, K.; Johnson, C.; Zhang, J.; Barrera, G.; Pili, Roberto.

In: Oncogene, Vol. 35, No. 12, 24.03.2016, p. 1541-1553.

Research output: Contribution to journalArticle

Ciamporcero, E, Shen, H, Ramakrishnan, S, Yu Ku, S, Chintala, S, Shen, L, Adelaiye, R, Miles, KM, Ullio, C, Pizzimenti, S, Daga, M, Azabdaftari, G, Attwood, K, Johnson, C, Zhang, J, Barrera, G & Pili, R 2016, 'YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage', Oncogene, vol. 35, no. 12, pp. 1541-1553. https://doi.org/10.1038/onc.2015.219
Ciamporcero E, Shen H, Ramakrishnan S, Yu Ku S, Chintala S, Shen L et al. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. Oncogene. 2016 Mar 24;35(12):1541-1553. https://doi.org/10.1038/onc.2015.219
Ciamporcero, E. ; Shen, H. ; Ramakrishnan, S. ; Yu Ku, S. ; Chintala, S. ; Shen, L. ; Adelaiye, R. ; Miles, K. M. ; Ullio, C. ; Pizzimenti, S. ; Daga, M. ; Azabdaftari, G. ; Attwood, K. ; Johnson, C. ; Zhang, J. ; Barrera, G. ; Pili, Roberto. / YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. In: Oncogene. 2016 ; Vol. 35, No. 12. pp. 1541-1553.
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