PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas

Abstract

Background & objectives:Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications.Methods:Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium.Results:Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P=0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium.Interpretation & conclusions:Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.

Safety and efficacy of sirolimus in recurrent intravenous leiomyomatosis, pulmonary benign metastatic leiomyomatosis, and leiomyomatosis peritonealis disseminata: a pilot study

“…In vitro experiments have confirmed that estradiol signaling can integrate a variety of extracellular signals and regulate various cellular functions, including cell growth, differentiation, transformation, and survival. Estradiol binds to the estrogen receptor and activates protein kinase pathways such as mitogen-activated protein kinase (MAPK) through the Ras-Raf-MEK-MAPK pathway and phosphatidylinositide 3-kinases (PI3K)–Akt through the PI3K–phosphatidylinositol-3,4,5-trisphosphate (PIP3)–Akt–mTOR pathway [ 25 – 27 ]. In the PI3K-PIP3-Akt-mTOR pathway, the binding of estradiol to receptors leads to the activation of PI3K, which in turn phosphorylates the plasma membrane lipid phosphatidylinositol-4,5-diphosphate to PIP3.…”

“…In the PI3K-PIP3-Akt-mTOR pathway, the binding of estradiol to receptors leads to the activation of PI3K, which in turn phosphorylates the plasma membrane lipid phosphatidylinositol-4,5-diphosphate to PIP3. This process leads to the recruitment and activation of Akt proteins, which regulate mTOR, glycogen synthase kinase 3, and other proteins [ 27 ]. This pathway regulates important processes, including the cell cycle, proliferation, and survival.…”

Differential regulatory effect of progesterone on the proliferation and apoptosis of uterine leiomyoma tissue explants and primary leiomyoma cell cultures

“…Thus, PTEN exerts tumor suppressive functions ( Keniry & Parsons, 2008 ) . It has been reported that PTEN mRNA expression was significantly increased in uterine leiomyoma tissue comparing to adjacent normal myometrium ( Makker et al ., 2016 ) . Increased PTEN activity in uterine leiomyomas might prevent the hyperactivation of the Akt pathway and produce benign tumor growth.…”

“…A known important negative regulator of Akt, tumor suppressor PTEN (phosphatase and tensin homolog), a non-redundant, evolutionarily conserved phosphatase, affects cell cycle progression, proliferation, chemotaxis and apoptosis (Keniry & Parsons, 2008). Expression of PTEN mRNA and protein levels was increased in uterine leiomyomas when com-pared to normal myometrium (Makker et al, 2016). Recent reports indicated that transcription factor PPARγ (peroxisome proliferator-activated receptor γ) transcriptionally up-regulates PTEN expression in tumor cells, with higher levels of expression of PPARγ mRNA seen in uterine leiomyomas when compared to adjacent normal myometrial tissue (Jeong et al, 2010).…”

Mechanisms of resistance to immune checkpoint inhibitors and strategies to reverse drug resistance in lung cancer

“…Some reports have described up-regulated expression of other T cell checkpoints at the time of acquired resistance, including T cell immunoglobulin mucin 3 (TIM-3), lymphocyte activation gene 3 (LAG3), and V-domain immunoglobulin suppressor of T cell activation (VISTA). By comparing the pathology before treatment with PD-1 inhibitor and the biopsy after drug resistance of uterine leiomyoma, it was found that drug-resistant tumor cells had unique double allelic PTEN gene deletion, and PD-1-positive T cell infiltration was reduced, [ 98 ] suggesting that MAPK and PTEN gene mutation may be one of the mechanisms of acquired resistance by ICIs. TIM-3 is highly expressed in the tumor microenvironment, which can promote the apoptosis of Teffs, mediate the proliferation of Tregs and inhibitory cells from bone marrow, and inhibit the functions of NK cells and DC cells, thus promoting the tumor immune escape.…”