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Review
. 2020 Aug 23;21(17):6073.
doi: 10.3390/ijms21176073.

Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies

Satoru Kyo  1 , Kentaro Nakayama  1
Affiliations
Review

Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies

Satoru Kyo et al. Int J Mol Sci. .

Abstract

Endometrial cancer (EC) is one of the most common malignancies of the female reproductive organs. The most characteristic feature of EC is the frequent association with metabolic disorders. However, the components of these disorders that are involved in carcinogenesis remain unclear. Accumulating epidemiological studies have clearly revealed that hyperinsulinemia, which accompanies these disorders, plays central roles in the development of EC via the insulin-phosphoinositide 3 kinase (PI3K) signaling pathway as a metabolic driver. Recent comprehensive genomic analyses showed that over 90% of ECs have genomic alterations in this pathway, resulting in enhanced insulin signaling and production of optimal tumor microenvironments (TMEs). Targeting PI3K signaling is therefore an attractive treatment strategy. Several clinical trials for recurrent or advanced ECs have been attempted using PI3K-serine/threonine kinase (AKT) inhibitors. However, these agents exhibited far lower efficacy than expected, possibly due to activation of alternative pathways that compensate for the PIK3-AKT pathway and allow tumor growth, or due to adaptive mechanisms including the insulin feedback pathway that limits the efficacy of agents. Overcoming these responses with careful management of insulin levels is key to successful treatment. Further interest in specific TMEs via the insulin PI3K-pathway in obese women will provide insight into not only novel therapeutic strategies but also preventive strategies against EC.

Keywords: PI3K-AKT; endometrial cancer; hyperglycemia; hyperinsulinemia; metabolic syndrome; tumor microenvironment.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Potential mechanisms of obesity-induced development of endometrial cancer (EC). Obesity induces increased aromatase expression and chronic low-grade inflammation in adipose tissues that play fundamental roles in EC development. The former results in increased estradiol (E2) production, and the latter triggers expression of various adipokines, cytokines, and chemokines, leading to insulin resistance. Insulin resistance causes hyperglycemia, which induces insulin synthesis in the spleen and lipogenesis in the liver. The former subsequently induces hyperinsulinemia, and the latter causes decreased expression of sex hormone-binding globulin (SHBG), leading to enhanced E2 activity. Hyperinsulinemia plays central roles in promoting EC growth via decreased insulin-like growth factor binding protein (IGFBP) 1 with enhanced insulin-like growth factor (IGF)-1 activity and most importantly, switching on of insulin-phosphoinositide 3 kinase (insulin-PI3K) signaling in EC cells. Δ4A: androstenedione, 17β-HSD: 17β-Hydroxysteroid dehydrogenases, T: testosterone, ER: estrogen receptor, adinoR1: adiponectin receptor 1, IR: insulin receptor, IGF1-R: insulin-like growth factor 1-receptor, HNF-4α: hepatocyte nuclear factor-4α. ↑ (up regulation), ↓ (down regulation), ⇢ (expected pathway).
Figure 2
Figure 2
Insulin-PI3K signaling facilitates cell proliferation and glucose metabolism via serine/threonine protein kinase B (AKT)-dependent and -independent mechanisms. The interaction of insulin with the insulin receptor (IR) triggers phosphoinositide 3-kinase (PI3K)-regulated signaling, in which phosphatidylinositol 3,4,5-triphosphate (PIP3) recruits phosphoinositide-dependent kinase 1 (PDK1), the serine/threonine kinase AKT, and other factors to the cell membrane where the signals are propagated via a series of serine/threonine kinase and tyrosine kinase activities. Phosphatase and tensin homologue (PTEN) can dephosphorylate PIP3 to form PIP2, limiting activation of this pathway, and loss-of-function mutations in PTEN cause significant elevations in PIP3, a driving force of this pathway. Phosphorylated AKT inhibits downstream targets via phosphorylation, including forkhead box protein O (FOXO)-1 and glycogen synthase kinase (GSK), both of which normally function to inhibit cell growth. Phosphorylated AKT also inhibits thioredoxin-interacting protein (TXNIP), an adaptor for endocytosis of glucose transporters (GLUTs), leading to dissociation from the GLUTs, inhibition of their endocytosis, and rapid glucose uptake upon insulin stimulation. AKT phosphorylation leads to activation of mammalian target of rapamycin (mTOR), a protein kinase that controls cell proliferation via activation of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP-1) complex and S6 kinase 1 (S6K1), which phosphorylates ribosomal S6 protein (rpS6). Insulin-PI3K signaling also activates an AKT-independent pathway, in which PIP3-recruited Ras-related C3 botulinus toxin substrate (RAC) activation leads to disruption of the actin cytoskeleton and release of filamentous actin (F-actin)-bound aldolase A (ALDOA), resulting in aldolase activation that promotes the glycolysis pathway. Additionally, PI3K signaling activates serum and glucocorticoid-induced protein kinase (SGK1) via PDK phosphorylation independent of AKT and can phosphorylate overlapping substrates of AKT, resulting in bypass of the AKT pathway. Metformin inhibits oxidative phosphorylation (OXPHOS) at the mitochondrial level, resulting in a decrease in the proton gradient across the inner mitochondrial membrane and leading to a reduction in proton-driven synthesis of adenosine triphosphate (ATP) and an increase in the ratio of cellular adenosine monophosphate (AMP) to ATP. This leads to preferential AMP binding to AMP-activated protein kinase (AMPK) and a conformational change that allows for phosphorylation/activation of AMPK by liver kinase B1 (LKB1). Activated AMPK converts cells to a catabolic state through AMPK-mediated phosphorylation, leading to the inhibition of downstream transcription factors involved in ATP-consuming synthetic pathways. AMPK activation also induces FOXO1 nuclear translocation, activating function of this protein. Additionally, activated AMPK inhibits mTOR to inhibit cell growth. IRS: insulin receptor substrate, p85: regulatory subunit of PI3K, p110: catalytic subunit of PI3K, NAD: nicotinamide adenine dinucleotide, LDH: lactate dehydrogenase, Acetyl-CoA: acetyl coenzyme A, TCA: tricarboxylic acid. → (activation), ⊣ (inhibition).
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