Abstract
While targeted non-small cell lung cancer (NSCLC) therapies improved outcome of defined disease subtypes, prognosis of most of the patients remains poor. We found the AAA+ ATPase Reptin to be highly expressed in the vast majority of 278 NSCLC tumour samples. Thus, the objective of the study was to assess the role of Reptin in NSCLC.
Survival analyses of 1,145 NSCLC patients revealed that high RNA expression levels of Reptin are associated with adverse outcome. Knock down of Reptin in human NSCLC cells impaired growth ex vivo and eliminated engraftment in a xenograft model. We uncovered direct interaction of Reptin with histone deacetylase 1 (HDAC1), as the critical mechanism driving NSCLC tumour progression. Pharmacological disruption of Reptin/HDAC1 complex resulted in substantial decrease of NSCLC cell proliferation and induced significant sensitization to cisplatin.
In conclusion, our results identify Reptin as a novel independent prognostic factor and as a key regulator mediating proliferation and clonal growth of human NSCLC cells ex vivo and in vivo. We unveil a Reptin/HDAC1 protein complex whose pharmacological disruption sensitizes NSCLC cells to cisplatin, suggesting this approach for application in clinical trials.
Abstract
The AAA+ ATPase Reptin confers tumour progression, resistance to chemotherapy and poor outcome in NSCLC patients
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Mikesch has nothing to disclose.
Conflict of interest: Dr. Schwammbach has nothing to disclose.
Conflict of interest: Dr. Hartmann has nothing to disclose.
Conflict of interest: Dr. Schmidt has nothing to disclose.
Conflict of interest: Dr. Schliemann has nothing to disclose.
Conflict of interest: Dr. Angenendt has nothing to disclose.
Conflict of interest: Dr. Wiewrodt has nothing to disclose.
Conflict of interest: Dr. Marra has nothing to disclose.
Conflict of interest: Dr. Thoennissen has nothing to disclose.
Conflict of interest: Prof. Wardelmann has nothing to disclose.
Conflict of interest: Dr. Köhler has nothing to disclose.
Conflict of interest: Prof. Lenz has nothing to disclose.
Conflict of interest: Prof. Müller-Tidow has nothing to disclose.
Conflict of interest: Prof. Berdel has nothing to disclose.
Conflict of interest: Dr. Arteaga-Paz has nothing to disclose.
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