Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines

Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The a...

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Autores principales:	I-Lun Hsin, Huang-Pin Shen, Hui-Yi Chang, Jiunn-Liang Ko, Po-Hui Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	c-Myc endometrial cancer mutant p53 dual PI3K/mTOR inhibitor PQR309 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/58d80cbb2c4f495cafe1e4d99e733926
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spelling	oai:doaj.org-article:58d80cbb2c4f495cafe1e4d99e7339262021-11-25T17:08:52ZSuppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines10.3390/cells101129162073-4409https://doaj.org/article/58d80cbb2c4f495cafe1e4d99e7339262021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2916https://doaj.org/toc/2073-4409Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The aim of this study is to evaluate the anticancer effect of PQR309 on endometrial cancer cells. PQR309 decreased cell viability in two-dimensional and three-dimensional cell culture models. PQR309 induced G1 cell cycle arrest and little cell death in endometrial cancer cell lines. It decreased CDK6 expression and increased p27 expression. Using the Proteome Profiler Human XL Oncology Array and Western blot assay, the dual inhibitor could inhibit the expressions of c-Myc and mtp53. KJ-Pyr-9, a c-Myc inhibitor, was used to prove the role of c-Myc in endometrial cancer survival and regulating the expression of mtp53. Knockdown of mtp53 lowered cell proliferation, Akt/mTOR pathway activity, and the expressions of c-Myc. mtp53 silence enhanced PQR309-inhibited cell viability, spheroid formation, and the expressions of p-Akt, c-Myc, and CDK6. This is the first study to reveal the novel finding of the PI3K/mTOR dual inhibitor in lowering cell viability by abolishing the PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop in endometrial cancer cell lines.I-Lun HsinHuang-Pin ShenHui-Yi ChangJiunn-Liang KoPo-Hui WangMDPI AGarticlec-Mycendometrial cancermutant p53dual PI3K/mTOR inhibitorPQR309Biology (General)QH301-705.5ENCells, Vol 10, Iss 2916, p 2916 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	c-Myc endometrial cancer mutant p53 dual PI3K/mTOR inhibitor PQR309 Biology (General) QH301-705.5
spellingShingle	c-Myc endometrial cancer mutant p53 dual PI3K/mTOR inhibitor PQR309 Biology (General) QH301-705.5 I-Lun Hsin Huang-Pin Shen Hui-Yi Chang Jiunn-Liang Ko Po-Hui Wang Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
description	Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The aim of this study is to evaluate the anticancer effect of PQR309 on endometrial cancer cells. PQR309 decreased cell viability in two-dimensional and three-dimensional cell culture models. PQR309 induced G1 cell cycle arrest and little cell death in endometrial cancer cell lines. It decreased CDK6 expression and increased p27 expression. Using the Proteome Profiler Human XL Oncology Array and Western blot assay, the dual inhibitor could inhibit the expressions of c-Myc and mtp53. KJ-Pyr-9, a c-Myc inhibitor, was used to prove the role of c-Myc in endometrial cancer survival and regulating the expression of mtp53. Knockdown of mtp53 lowered cell proliferation, Akt/mTOR pathway activity, and the expressions of c-Myc. mtp53 silence enhanced PQR309-inhibited cell viability, spheroid formation, and the expressions of p-Akt, c-Myc, and CDK6. This is the first study to reveal the novel finding of the PI3K/mTOR dual inhibitor in lowering cell viability by abolishing the PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop in endometrial cancer cell lines.
format	article
author	I-Lun Hsin Huang-Pin Shen Hui-Yi Chang Jiunn-Liang Ko Po-Hui Wang
author_facet	I-Lun Hsin Huang-Pin Shen Hui-Yi Chang Jiunn-Liang Ko Po-Hui Wang
author_sort	I-Lun Hsin
title	Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
title_short	Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
title_full	Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
title_fullStr	Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
title_full_unstemmed	Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
title_sort	suppression of pi3k/akt/mtor/c-myc/mtp53 positive feedback loop induces cell cycle arrest by dual pi3k/mtor inhibitor pqr309 in endometrial cancer cell lines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/58d80cbb2c4f495cafe1e4d99e733926
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Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines

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