Steroid Receptor Coactivator-2 Controls the Pentose Phosphate Pathway through RPIA in Human Endometrial Cancer Cells

Szwarc, Maria M.; Kommagani, Ramakrishna; Putluri, Vasanta; Dubrulle, Julien; Stossi, Fabio; Mancini, Michael A.; Coarfa, Cristian; Lanz, Rainer B.; Putluri, Nagireddy; DeMayo, Francesco J.; Lydon, John P.; O’Malley, Bert W.

doi:10.1038/s41598-018-31372-y

Cited by 8 publications

(5 citation statements)

References 51 publications

(50 reference statements)

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“…The question is raised because SRC-2 (along with other SRC members) is an established coregulator of carbohydrate, lipid, and amino acid metabolism in other physiological systems ( Stashi et al, 2014 ; O’Malley, 2020 ). Furthermore, SRC-2 in human endometrial cancer cells was recently shown to be essential for the normal performance of the pentose phosphate pathway in addition to maintaining cellular glycolytic capacity and oxidative phosphorylation ( Szwarc et al, 2018b ). As an anabolic multi-enzyme pathway, the pentose phosphate pathway generates NADPH for reductive biosynthesis as well as pentoses (including ribose 5-phosphate) to generate nucleotides for DNA and RNA synthesis.…”

Section: Modifiers Of Pgr Mediated Responses In the Endometrial Epithmentioning

confidence: 99%

“…As an anabolic multi-enzyme pathway, the pentose phosphate pathway generates NADPH for reductive biosynthesis as well as pentoses (including ribose 5-phosphate) to generate nucleotides for DNA and RNA synthesis. Together, these SRC-2 dependent pathways are required to drive rapid proliferation and anchorage independent growth of this cancer cell type ( Szwarc et al, 2018b ). Whether SRC-2 is also required for pentose phosphate pathway functionality in normal human endometrial cells awaits investigation; (2) Is impaired control of the glycolytic pathway an underpinning for the implicated role of SRC-2 in endometrial pathologies as observed in patients with polycystic ovary syndrome or endometrial cancer?…”

Section: Modifiers Of Pgr Mediated Responses In the Endometrial Epithmentioning

confidence: 99%

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Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Maurya

DeMayo

Lydon

2021

Front. Cell Dev. Biol.

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Synchrony between progesterone-driven endometrial receptivity and the arrival of a euploid blastocyst is essential for embryo implantation, a prerequisite event in the establishment of a successful pregnancy. Advancement of embryo implantation within the uterus also requires stromal fibroblasts of the endometrium to transform into epithelioid decidual cells, a progesterone-dependent cellular transformation process termed decidualization. Although progesterone is indispensable for these cellular processes, the molecular underpinnings are not fully understood. Because human studies are restricted, much of our fundamental understanding of progesterone signaling in endometrial periimplantation biology comes from in vitro and in vivo experimental systems. In this review, we focus on the tremendous progress attained with the use of engineered mouse models together with high throughput genome-scale analysis in disclosing key signals, pathways and networks that are required for normal endometrial responses to progesterone during the periimplantation period. Many molecular mediators and modifiers of the progesterone response are implicated in cross talk signaling between epithelial and stromal cells of the endometrium, an intercellular communication system that is critical for the ordered spatiotemporal control of embryo invasion within the maternal compartment. Accordingly, derailment of these signaling systems is causally linked with infertility, early embryo miscarriage and gestational complications that symptomatically manifest later in pregnancy. Such aberrant progesterone molecular responses also contribute to endometrial pathologies such as endometriosis, endometrial hyperplasia and cancer. Therefore, our review makes the case that further identification and functional analysis of key molecular mediators and modifiers of the endometrial response to progesterone will not only provide much-needed molecular insight into the early endometrial cellular changes that promote pregnancy establishment but lend credible hope for the development of more effective mechanism-based molecular diagnostics and precision therapies in the clinical management of female infertility, subfertility and a subset of gynecological morbidities.

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Section: Modifiers Of Pgr Mediated Responses In the Endometrial Epithmentioning

confidence: 99%

Section: Modifiers Of Pgr Mediated Responses In the Endometrial Epithmentioning

confidence: 99%

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Maurya

DeMayo

Lydon

2021

Front. Cell Dev. Biol.

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“…Using the timed natural pregnancy model, we reveal here that SRC‐2 is pivotal for the PMT changes that must occur in the luminal epithelium to enable embryo attachment and adherence within the context of a receptive uterus. Given the cell‐type specific roles of SRC‐2 in endometrial biology and pathobiology 10,19,20,25,83,84 and the knowledge‐gap associated with early pregnancy establishment, our findings provide a foundation for further investigations into the specific involvement of this coregulator in the endometrial epithelium in ensuring normal endometrial function and health.…”

Section: Discussionmentioning

confidence: 88%

Steroid receptor coactivator‐2 drives epithelial reprogramming that enables murine embryo implantation

Maurya,

Szwarc,

Lonard

et al. 2023

The FASEB Journal

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Although we have shown that steroid receptor coactivator‐2 (SRC‐2), a member of the p160/SRC family of transcriptional coregulators, is essential for decidualization of both human and murine endometrial stromal cells, SRC‐2's role in the earlier stages of the implantation process have not been adequately addressed. Using a conditional SRC‐2 knockout mouse (SRC‐2d/d) in timed natural pregnancy studies, we show that endometrial SRC‐2 is required for embryo attachment and adherence to the luminal epithelium. Implantation failure is associated with the persistent expression of Mucin 1 and E‐cadherin on the apical surface and basolateral adherens junctions of the SRC‐2d/d luminal epithelium, respectively. These findings indicate that the SRC‐2d/d luminal epithelium fails to exhibit a plasma membrane transformation (PMT) state known to be required for the development of uterine receptivity. Transcriptomics demonstrated that the expression of genes involved in steroid hormone control of uterine receptivity were significantly disrupted in the SRC‐2d/d endometrium as well as genes that control epithelial tight junctional biology and the emergence of the epithelial mesenchymal transition state, with the latter sharing similar biological properties with PMT. Collectively, these findings uncover a new role for endometrial SRC‐2 in the induction of the luminal epithelial PMT state, which is a prerequisite for the development of uterine receptivity and early pregnancy establishment.

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“…Kras promotes glycolysis intermediates and non-oxidative PPP in pancreatic tumors, and blocking the non-oxidative PPP by the knockdown of RPIA or RPE in the tumor cells inhibits tumor growth [ 14 ]. In addition, RPIA is involved in liver cancer [ 15 , 16 ], colorectal cancer [ 17 , 18 ] and endometrial cancer [ 19 ]. However, the role of RPIA in lung cancer remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Ribose-5-Phosphate Isomerase a Induces ROS to Activate Autophagy, Apoptosis, and Cellular Senescence in Lung Cancer

Nieh

Chou

Wang

et al. 2022

IJMS

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Ribose-5-phosphate isomerase A (RPIA) regulates tumorigenesis in liver and colorectal cancer. However, the role of RPIA in lung cancer remains obscure. Here we report that the suppression of RPIA diminishes cellular proliferation and activates autophagy, apoptosis, and cellular senescence in lung cancer cells. First, we detected that RPIA protein was increased in the human lung cancer versus adjust normal tissue via tissue array. Next, the knockdown of RPIA in lung cancer cells displayed autophagic vacuoles, enhanced acridine orange staining, GFP-LC3 punctae, accumulated autophagosomes, and showed elevated levels of LC3-II and reduced levels of p62, together suggesting that the suppression of RPIA stimulates autophagy in lung cancer cells. In addition, decreased RPIA expression induced apoptosis by increasing levels of Bax, cleaved PARP and caspase-3 and apoptotic cells. Moreover, RPIA knockdown triggered cellular senescence and increased p53 and p21 levels in lung cancer cells. Importantly, RPIA knockdown elevated reactive oxygen species (ROS) levels. Treatment of ROS scavenger N-acetyl-L-cysteine (NAC) reverts the activation of autophagy, apoptosis and cellular senescence by RPIA knockdown in lung cancer cells. In conclusion, RPIA knockdown induces ROS levels to activate autophagy, apoptosis, and cellular senescence in lung cancer cells. Our study sheds new light on RPIA suppression in lung cancer therapy.

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Steroid Receptor Coactivator-2 Controls the Pentose Phosphate Pathway through RPIA in Human Endometrial Cancer Cells

Cited by 8 publications

References 51 publications

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Steroid receptor coactivator‐2 drives epithelial reprogramming that enables murine embryo implantation

Suppression of Ribose-5-Phosphate Isomerase a Induces ROS to Activate Autophagy, Apoptosis, and Cellular Senescence in Lung Cancer

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