Cargando…

Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB

Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chl...

Descripción completa

Detalles Bibliográficos
Autores principales: Cui, Yunxia, Wu, Huiwen, Yang, Linlin, Huang, Ting, Li, Jian, Gong, Xiaodi, Li, Lijuan, Sun, Xiao, Mao, Fei, Wang, Yudong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087176/
https://www.ncbi.nlm.nih.gov/pubmed/33937078
http://dx.doi.org/10.3389/fonc.2021.665832
_version_ 1783686625056784384
author Cui, Yunxia
Wu, Huiwen
Yang, Linlin
Huang, Ting
Li, Jian
Gong, Xiaodi
Li, Lijuan
Sun, Xiao
Mao, Fei
Wang, Yudong
author_facet Cui, Yunxia
Wu, Huiwen
Yang, Linlin
Huang, Ting
Li, Jian
Gong, Xiaodi
Li, Lijuan
Sun, Xiao
Mao, Fei
Wang, Yudong
author_sort Cui, Yunxia
collection PubMed
description Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.
format Online
Article
Text
id pubmed-8087176
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-80871762021-05-01 Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB Cui, Yunxia Wu, Huiwen Yang, Linlin Huang, Ting Li, Jian Gong, Xiaodi Li, Lijuan Sun, Xiao Mao, Fei Wang, Yudong Front Oncol Oncology Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients. Frontiers Media S.A. 2021-04-16 /pmc/articles/PMC8087176/ /pubmed/33937078 http://dx.doi.org/10.3389/fonc.2021.665832 Text en Copyright © 2021 Cui, Wu, Yang, Huang, Li, Gong, Li, Sun, Mao and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Cui, Yunxia
Wu, Huiwen
Yang, Linlin
Huang, Ting
Li, Jian
Gong, Xiaodi
Li, Lijuan
Sun, Xiao
Mao, Fei
Wang, Yudong
Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title_full Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title_fullStr Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title_full_unstemmed Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title_short Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
title_sort chlorpromazine sensitizes progestin-resistant endometrial cancer cells to mpa by upregulating prb
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087176/
https://www.ncbi.nlm.nih.gov/pubmed/33937078
http://dx.doi.org/10.3389/fonc.2021.665832
work_keys_str_mv AT cuiyunxia chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT wuhuiwen chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT yanglinlin chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT huangting chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT lijian chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT gongxiaodi chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT lilijuan chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT sunxiao chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT maofei chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb
AT wangyudong chlorpromazinesensitizesprogestinresistantendometrialcancercellstompabyupregulatingprb