Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53

Silvia Licciulli, Jacqueline L. Avila, Linda Hanlon, Scott Troutman, Matteo Cesaroni, Smitha Kota, Brian Keith, M. Celeste Simon, Ellen Puré, Fred Radtke, Anthony J Capobianco, Joseph L. Kissil

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Abstract

The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is a putative oncogene in non-small cell lung cancer (NSCLC) and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma, we directly assessed its requirement in Kras-induced tumorigenesis in vivo using an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic Kras and deletion of Notch1. We found that Notch1 function is required for tumor initiation via suppression of p53-mediated apoptosis through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in Kras-driven lung adenocarcinoma and as a regulator of p53 at a posttranslational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in patients with NSCLC carrying wild-type p53. This information is critical for design and implementation of new therapeutic strategies in this cohort of patients representing 50% of NSCLC cases.

Original languageEnglish
Pages (from-to)5974-5984
Number of pages11
JournalCancer Research
Volume73
Issue number19
DOIs
StatePublished - Oct 1 2013

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Non-Small Cell Lung Carcinoma
Cell Survival
Neoplasms
Oncogenes
Carcinogenesis
Apoptosis
Adenocarcinoma of lung
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Licciulli, S., Avila, J. L., Hanlon, L., Troutman, S., Cesaroni, M., Kota, S., ... Kissil, J. L. (2013). Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Research, 73(19), 5974-5984. https://doi.org/10.1158/0008-5472.CAN-13-1384

Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. / Licciulli, Silvia; Avila, Jacqueline L.; Hanlon, Linda; Troutman, Scott; Cesaroni, Matteo; Kota, Smitha; Keith, Brian; Simon, M. Celeste; Puré, Ellen; Radtke, Fred; Capobianco, Anthony J; Kissil, Joseph L.

In: Cancer Research, Vol. 73, No. 19, 01.10.2013, p. 5974-5984.

Research output: Contribution to journalArticle

Licciulli, S, Avila, JL, Hanlon, L, Troutman, S, Cesaroni, M, Kota, S, Keith, B, Simon, MC, Puré, E, Radtke, F, Capobianco, AJ & Kissil, JL 2013, 'Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53', Cancer Research, vol. 73, no. 19, pp. 5974-5984. https://doi.org/10.1158/0008-5472.CAN-13-1384
Licciulli S, Avila JL, Hanlon L, Troutman S, Cesaroni M, Kota S et al. Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Research. 2013 Oct 1;73(19):5974-5984. https://doi.org/10.1158/0008-5472.CAN-13-1384
Licciulli, Silvia ; Avila, Jacqueline L. ; Hanlon, Linda ; Troutman, Scott ; Cesaroni, Matteo ; Kota, Smitha ; Keith, Brian ; Simon, M. Celeste ; Puré, Ellen ; Radtke, Fred ; Capobianco, Anthony J ; Kissil, Joseph L. / Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. In: Cancer Research. 2013 ; Vol. 73, No. 19. pp. 5974-5984.
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