Nek6 and Hif-1α cooperate with the cytoskeletal gateway of drug resistance to drive outcome in serous ovarian cancer.
Hypoxia selects the most aggressive and drug-resistant clones in solid malignancies. One of the pivotal transcription factors induced by hypoxia is Hif-1α. However, in serous ovarian cancer (SEOC), Hif-1α expression is not a prognostic biomarker. This study aims to assess the hypothesis that the serine-threonine kinase Nek6 functions as a downstream effector cooperating with Hif-1α in driving ovarian cancer aggressiveness. Nek6 was overexpressed and Hif-1α was silenced in A2780 cells. Nek6 was also stably silenced in Hey cells. The dependence of Nek6 expression on Hif-1α was assayed as a function of hypoxic growth conditions. Nek6 interaction with the cytoskeletal gateway of drug resistance was investigated with far western blot. The co-expression of NEK6, HIF1A, TUBB3 and GBP1 transcripts was quantified with qPCR in two cohorts of SEOC patients (346 locally treated patients and 344 from the TCGA dataset). Nek6 expression is induced by hypoxia in a Hif-1α dependent fashion. Nek6 directly interacts with GBP-1, thus being a component of the cytoskeletal gateway of drug resistance. Nek6 overexpression increases and silencing decreases the anchorage-independent growth of cultured cells. In SEOC patients, NEK6 expression is significantly correlated with HIF1A. Co-expression of NEK6, HIF1A, TUBB3 and GBP1 transcripts identifies a subset of SEOC patients characterized by poor outcome and drug resistance. This study demonstrates the functional relevance of Nek6 in the context of the adaptive response to hypoxia in SEOC. This finding may help identify a sub-population of patients at high risk of relapse to standard first-line chemotherapy.
Department of Gynecology, Catholic University of The Sacred Heart Largo Agostino Gemelli 8. 00168 Rome, Italy.
Marta De
MD
Donato
Laboratory of Molecular Oncology, Jean Paul IInd Research Foundation Largo Agostino Gemelli 1. 86100 Campobasso, Italy.
Mara
M
Fanelli
Danbury Hospital Research Institute 131 West Street 06810 Danbury, CT, USA.
Marisa
M
Mariani
Department of Gynecology, Catholic University of The Sacred Heart Largo Agostino Gemelli 8. 00168 Rome, Italy.
Giuseppina
G
Raspaglio
Danbury Hospital Research Institute 131 West Street 06810 Danbury, CT, USA.
Deep
D
Pandya
Danbury Hospital Research Institute 131 West Street 06810 Danbury, CT, USA.
Shiquan
S
He
Danbury Hospital Research Institute 131 West Street 06810 Danbury, CT, USA.
Paul
P
Fiedler
Department of Gynecology, Catholic University of The Sacred Heart Largo Agostino Gemelli 8. 00168 Rome, Italy.
Marco
M
Petrillo
Department of Gynecology, Catholic University of The Sacred Heart Largo Agostino Gemelli 8. 00168 Rome, Italy.
Giovanni
G
Scambia
Danbury Hospital Research Institute 131 West Street 06810 Danbury, CT, USA.
Cristiano
C
Ferlini
GBP-1; Hif-1-alpha; Nek6; Ovarian cancer; class III beta-tubulin