TRAP1 regulates autophagy in lung cancer cells
es A. Barbosa
Ana F. Branco
Patricia M. Scott
Paulo J. Oliveira
CNC-Center for Neuroscience and Cell
Biology, UC-Biotech, University of
Coimbra, Cantanhede, Portugal
Department of Morphology and Cell
Biology, University of Oviedo, Oviedo,
Department of Biomedical Sciences,
University of Minnesota Medical School,
Duluth, MN, USA
Paulo J. Oliveira, CNC—Center for
Neuroscience and Cell Biology, University
of Coimbra UC-Biotech, Biocant Park,
Lot 8A, Cantanhede, Portugal.
European Regional Development Fund
(ERDF) through the COMPETE 2020—
Operational Programme for
Competitiveness and Internationalisation,
and Portuguese national funds via FCT—
ao para a Ci
encia e a Tecnologia,
Grant/Award Number: POCI-01-0145-
FEDER-016390 (CANCELSTEM), IF/
007440; PCTI project (Government of the
Principality of Asturias and ERDF), Grant/
Award Number: GRUPIN14-071
Background: Expression of TRAP1, a member of the HSP90 chaperone family,
has been implicated in tumour protective effects, based on its differential mito-
chondrial localization and function.
Design: This work was designed to provide new insights into the pathways
involved in TRAP1-provided cytoprotection on NSCLC. For this, TRAP1-
depleted A549 human NSCLC cells and MRC-5 normal lung fibroblasts were
produced using a siRNA approach and main cellular quality control mechanisms
Results: TRAP1-depleted A549 cells displayed decreased cell viability likely due
to impaired mitochondrial function including decreased ATP/AMP ratio, oxygen
consumption and membrane potential, as well as increased apoptotic indicators.
Furthermore, the negative impact of TRAP1 depletion on mitochondrial function
was not observed in normal MRC-5 lung cells, which might be due to the differ-
ential intracellular localization of the chaperone in tumour versus normal cells.
Additionally, A549 TRAP1-depleted cells showed increased autophagic flux.
Functionally, autophagy inhibition resulted in decreased cell viability in both
TRAP1-expressing and TRAP1-depleted tumour cells with minor effects on
MRC-5 cells. Conversely, autophagy stimulation decreased cell viability of both
A549 and MRC-5 TRAP1-expressing cells while in A549 TRAP1-depleted cells,
increased autophagy augmented viability.
Conclusions: Our results show that even though TRAP1 depletion affects both
normal MRC-5 and tumour A549 cell proliferation, inhibition of autophagy per
se led to a decrease in tumour cell mass, while having a reduced effect on the
normal cell line. The strategy of targeting TRAP1 in NSCLC shows future poten-
tial therapeutic applications.
apoptosis, autophagy, cathepsin B, lung cancer, macroautophagy, TRAP1
Tumour Necrosis Factor Receptor-Associated Protein 1
(TRAP1) is a member of the HSP90 family with predomi-
nantly mitochondrial localization, whose cytoprotective role
has been widely documented.
Several studies suggest
that TRAP1 preserves cellular function by protecting mito-
chondrial function, limiting the effects of oxidative stress
either by decreasing reactive oxygen species (ROS)-
or by attenuating ROS production
Received: 3 January 2018
Accepted: 20 January 2018
Eur J Clin Invest. 2018;48:e12900.
wileyonlinelibrary.com/journal/eci © 2018 Stichting European Society for Clinical
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