PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy

Liu, Hua; Zhang, Liqin; xu-yan, zhang; Cui, Zhonghui

doi:10.2147/ott.s95267

Cited by 62 publications

(51 citation statements)

References 24 publications

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“…In type I endometrial cancer, as autophagy is repressed by activated PI3K/AKT/mTOR signaling pathway, the proliferation of tumor cells becomes facilitated, indicating that autophagy inhibits the development of tumors. Hua Liu, et al showed that activation of the PI3K/AKT pathway could result in activation of mTOR and the proliferation of endometrial cells by inhibiting autophagy [18]. Currently, autophagy is considered as a "double-edged sword", since it not only inhibits tumor progression by depriving cells of nutrients and energy, but also promotes tumor progression by conferring cells with nutrients and energy [19,20].…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients

Wang

Liu

et al. 2020

Preprint

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Background : Autophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC.Methods : First, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariat, LASSO, and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, gene set enrichment and somatic mutation analyses were also used for these prognostic autophagy-related genes.Results : A total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into highrisk and low-risk groups (P<0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group.Gene set enrichment analysis revealed high risk score was associated with tumor initiation and progression associated pathways.Conclusions : Based on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics. * Hui Wang, Xiaoling Ma, and Jinhui Liu contributed equally to this work Background As an evolutionarily ancient and highly conserved biological behavior, autophagy plays a

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Section: Discussionmentioning

confidence: 99%

Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients

Wang

Liu

et al. 2020

Preprint

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“…Aberrant PI3K/AKT signalling has been described in many human cancers, including soft tissue sarcomas [51][52][53][54][55][56][57], and AKT activation contributes to pathways that promote tumour cell proliferation, invasion and metastasis [58,59]. Indeed, there is compelling evidence that a key requirement for the development of RMS is the prolonged activation of serine/threonine kinases such as AKT [60].…”

Section: Introductionmentioning

confidence: 99%

The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma

Sims

Maranyane

Damerell

et al. 2020

Cancers

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Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.

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“…With an increasing number of women electing to delay childbearing, there is a critical need for adequate treatment without hysterectomy for nulliparous women with EC (3). Progestins, are widely used in young early EC patients as conservative endocrine treatment (4). Progesterone, a tumor suppressor in the endometrium, plays a critical role in cell differentiation, cycle, and apoptosis (5).…”

Section: Introductionmentioning

confidence: 99%

“…Progesterone, a tumor suppressor in the endometrium, plays a critical role in cell differentiation, cycle, and apoptosis (5). Approximately 90% of young patients can be treated with progestin due to a high expression of progesterone receptor (PR), which often results in a good prognosis (4). A meta-analysis indicates that 72 percent of patients achieved remission by oral progesterone, and the pregnancy outcome is about 35-40% (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…However, a follow-up study shows that 35.4% of patients treated with progesterone have a recurrence after an initial response (p = 0.03), and 25.4% of them suffer persistent disease (p = 0.02) (8). In addition, according to clinical data, 30 percent of young patients fail to respond to progestin due to the possessed drug resistance during progestin treatment (4), and in turn, receptor-negative patients have been reported to respond to hormone treatment (7,9). Accordingly, drug resistance is a major challenge during the treatment of endometrial cancer.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of Circular RNA Expression in Ishikawa Human Endometrial Carcinoma Cells with Progesterone Treatment

Wang¹,

Zheng²,

Cao³

et al. 2020

Preprint

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Background Progestins are commonly used as the conservative endocrine treatment of young early endometrial cancer (EC) patients. Circular RNAs (circRNAs) are new group players in multiple cellular functions. This study aims to identify the differentially expressed circular RNAs (DE-circRNAs) in endometrial cancer (EC) cells upon the progesterone treatment, aiding in the understanding of the impact of circRNAs in progestin therapy. Methods RNA-seq analysis was used to identify the DE-circRNAs between MPA-treated and -non-treated Ishikawa cell lines. Functional enrichment analysis and circRNA-miRNA interaction network analysis were applied to these DE-circRNAs, validated by qRT-PCR analyses. Moreover, shRNA knockdown was utilized to explore the circRNA function. Results A total of 87 circRNAs were differentially expressed in Ishikawa cell lines with MPA treatment compared with that of control cells (|fold change| ≥2.0, p < 0.05). Besides, these circRNAs were mainly enriched in cancer-related pathways, including response to cholesterol, epithelial to mesenchymal transition, and base-excision repair. The competing endogenous RNA (ceRNA) network showed that miR-296-3p, miR-1236-3p, and miR-144-5p were related to cancer. Furthermore, the qPCR results were coincident with the RNA-seq data. Of note, hsa_circ_0001860 was significantly induced upon MPA treatment. Knockdown of hsa_circ_0001860 can partially rescue the MPA-inhibited cell proliferation and invasion and regulate the expression of its interacting miRNAs. Conclusions This is the first time to evaluate the circRNA expression profile in progesterone treatment for EC. These circRNAs (e.g., hsa_circ_0001860) may be used as potential diagnostic biomarkers and treatment targets for the evaluation of EC progesterone treatment.

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PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy

Cited by 62 publications

References 24 publications

Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients

Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients

The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma

Characteristics of Circular RNA Expression in Ishikawa Human Endometrial Carcinoma Cells with Progesterone Treatment

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