COMMENTARY
Sestrin family of genes and their role in cancer-related fatigue
Velda J. Gonzalez-Mercado
1
&
Brooke L. Fridley
2
&
Leorey N. Saligan
3
Received: 13 July 2017 / Accepted: 2 March 2018 / Published online: 12 March 2018
#
Springer-Verlag GmbH Germany, part of Springer Nature 2018
Cancer-related fatigue (CRF) continues to be a prevalent and
distressing symptom experienced by cancer patients and sur-
vivors. CRF is defined by the National Comprehensive
Cancer Network as a Bdistressing, persistent, subjective sense
of tiredness or exhaustion related to cancer or cancer treatment
that is not proportional to recent activity and that interferes
with usual functioning [1].^ Although there is currently no
optimal management and scant molecular evidence to guide
the development of effective CRF therapies, several patho-
physiological mechanisms have been proposed to explain
the development of CRF [2, 3]. These pathophysiological
mechanisms of CRF are believed to be complex and involve
a cascade of events including the dysregulation of several
physiological and biochemical systems, such as oxidative
stress, inflammation, immune modulation, circadian rhythms
modulation, growth factors, serotonin dysregulation,
hypothalamic-pituitary-adrenal-axis disruption, vagal afferent
activation, and hematopoietic dysfunction [2–4]. Although
these proposed mechanisms of CRF pathophysiology are yet
to be independently investigated, recent evidence suggest a
critical role of mitochondrial dysfunction/oxidative stress in
CRF [4, 5].
Association of oxidative stress with cancer
and CRF
Cancer and CRF have both been associated with oxidative
stress and genomic instability [4–6]. The prominent feature
of cancer cells is their metabolic transformation, which is their
reckless acquisition of energy [7]. Briefly, this metabolic
transformation in cancer cells demands a rapid supply of aden-
osine triphosphate (ATP) through the unquenchable consump-
tion of glucose, depleting the mitochondria with available ox-
ygen and resulting in the overproduction of mitochondrial
reactive oxygen species (ROS) triggering the excessive accu-
mulation of mitochondrial-driven oxidative stress [7, 8]. In
addition, extrinsic factors such as radiation therapy and che-
motherapy could contribute to the accumulation of oxidative
stress [9]. Accumulation of oxidative stress is the reflection of
the inability of the mitochondria to detoxify ROS [9].
Intracellular ROS can influence cellular processes such as cell
growth [8, 10]. The accumulation of ROS in the mitochondria
has been linked as an apoptotic stimulus [10] and has been
associated with CRF [11, 12].
Dysfunctional mitochondria related to cancer and its treat-
ment can impair the cell’s ability to detoxify ROS, reactive
nitrogen species (RNS), and other reactive metabolic interme-
diates [8, 13], shifting mitochondrial respiration to a more
glycolytic source, reducing the supply of ATP [3, 4].
Reduced ATP supply deprives the cell of nutrients and energy
which is believed to contribute to CRF development or inten-
sification [3–5]. The link between reduced ATP supply and
fatigue has been supported by prior exhaustive reviews [3, 4].
The Sestrin family of genes
Understanding the role of genomics in cancer and in CRF is an
expanding area of investigation. For example, concomitant
overexpressions of the genes ERα36, EGFR,andHER2 were
* Velda J. Gonzalez-Mercado
veldag@health.usf.edu
Brooke L. Fridley
Brooke.Fridley@moffitt.org
Leorey N. Saligan
saliganl@mail.nih.gov
1
College of Nursing, University of South Florida, 12901 Bruce B.
Downs Blvd., MDC22, Tampa, FL 33612-4766, USA
2
Department of Biostatistics & Bioinformatics, Moffitt Cancer Center,
Tampa, FL, USA
3
Symptoms Biology Unit, National Institute of Nursing Research at
the National Institute of Health, Bethesda, MD, USA
Supportive Care in Cancer (2018) 26:2071–2074
https://doi.org/10.1007/s00520-018-4139-8
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