Abstract
BackgroundThe sestrin family of stress-responsive genes (SESN1-3) are suggested to be involved in regulation of metabolism and aging through modulation of the AMPK-mTOR pathway. AMP-activated protein kinase (AMPK) is an effector of the tumour suppressor LKB1, which regulates energy homeostasis, cell polarity, and the cell cycle. SESN1/2 can interact directly with AMPK in response to stress to maintain genomic integrity and suppress tumorigenesis. Ionizing radiation (IR), a widely used cancer therapy, is known to increase sestrin expression, and acutely activate AMPK. However, the regulation of AMPK expression by sestrins in response to IR has not been studied in depth.Methods and FindingsThrough immunoprecipitation we observed that SESN2 directly interacted with the AMPKα1β1γ1 trimer and its upstream regulator LKB1 in MCF7 breast cancer cells. SESN2 overexpression was achieved using a Flag-tagged SESN2 expression vector or a stably-integrated tetracycline-inducible system, which also increased AMPKα1 and AMPKβ1 subunit phosphorylation, and co-localized with phosphorylated AMPKα-Thr127 in the cytoplasm. Furthermore, enhanced SESN2 expression increased protein levels of LKB1 and AMPKα1β1γ1, as well as mRNA levels of LKB1, AMPKα1, and AMPKβ1. Treatment of MCF7 cells with IR elevated AMPK expression and activity, but this effect was attenuated in the presence of SESN2 siRNA. In addition, elevated SESN2 inhibited IR-induced mTOR signalling and sensitized MCF7 cells to IR through an AMPK-dependent mechanism.ConclusionsOur results suggest that in breast cancer cells SESN2 is associated with AMPK, it is involved in regulation of basal and IR-induced expression and activation of this enzyme, and it mediates sensitization of cancer cells to IR.
Highlights
In various malignancies including breast cancer, mitogen activated signals can become constitutively activated leading to increased metabolism and genotoxic stress [1]
Our results suggest that in breast cancer cells SESN2 is associated with AMPK, it is involved in regulation of basal and Ionizing radiation (IR)-induced expression and activation of this enzyme, and it mediates sensitization of cancer cells to IR
We examined the effect of SESN2 overexpression, IR, or the combined treatment on the activity of the Akt/mTOR survival pathway (Figure 4A–B)
Summary
In various malignancies including breast cancer, mitogen activated signals can become constitutively activated leading to increased metabolism and genotoxic stress [1]. There are various cellular compensatory mechanisms that respond genomic stress, including the tumour suppressor p53, which suppresses cell growth and propagation through the induction of numerous target genes [2]. Some products of p53 activation that are important in mediating stress-signalling include AMP-activated protein kinase (AMPK), Tuberous sclerosis 2 (TSC2), and sestrin1/2 (SESN1/2) [3,4]. Mammalian SESN1/2 was shown to act as a scaffolding protein and form an active complex with AMPK and TSC2 to block mammalian-TOR (mTOR) signalling in response to genotoxic stress [4]. The sestrin family of stress-responsive genes (SESN1-3) are suggested to be involved in regulation of metabolism and aging through modulation of the AMPK-mTOR pathway. The regulation of AMPK expression by sestrins in response to IR has not been studied in depth
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