Mifepristone inhibits proliferation, migration and invasion of HUUA cells and promotes its apoptosis by regulation of FAK and PI3K/AKT signaling pathway

Purpose The aim was to investigate mifepristone effects on endometrial carcinoma and the related mechanism. Methods HHUA cells were treated with DMEM containing different concentrations of mifepristone. HHUA cells treated with 100 μmol/L mifepristone were named the Mifepristone group. HHUA cells co-transfected with pcDNA3.1-PI3K and pcDNA3.1-AKT overexpression vectors were treated with 100 μmol/L mifepristone and named the Mifepristone + PI3K/AKT group. mRNA expression was detected by quantitative reverse transcription PCR. Protein expression was performed by Western blot. Cell proliferation was conducted by MTT assay. Wound-healing assay was conducted. Transwell was used to detect cells migration and invasion. Apoptosis detection was performed by flow cytometry. Results Mifepristone inhibited HHUA cells proliferation in a dose-dependent manner. Compared with HHUA cells treated with 0 μmol/L mifepristone, HHUA cells treated by 50–100 μmol/L mifepristone had a lower wound-healing rate, a greater number of migrating and invasive cells (P<0.01), as well as a higher percentage of apoptotic cells and Caspase-3 expression (P<0.01). When HHUA cells were treated with 50–100 μmol/L of mifepristone, FAK, p-FAK, p-PI3K and p-AKT relative expression was all significantly lower than HHUA cells treated with 0 μmol/L of mifepristone (P<0.01). Compared with the Mifepristone group, HHUA cells of the Mifepristone + PI3K/AKT group had a lower cell growth inhibition rate and percentage of apoptotic cells (P<0.01). Conclusion Mifepristone inhibited HUUA cells proliferation, migration and invasion and promoted its apoptosis by regulation of FAK and PI3K/AKT signaling pathway.

[1]  F. Fanfani,et al.  Endometrial , 2020, Definitions.

[2]  C. Telleria,et al.  Advanced assessment of migration and invasion of cancer cells in response to mifepristone therapy using double fluorescence cytochemical labeling , 2019, BMC Cancer.

[3]  A. Molinolo,et al.  Abstract OT1-04-02: Mifepristone treatment for breast cancer patients expressing levels of progesterone receptor isoform A (PRA) higher than those of isoform B (PRB) , 2018 .

[4]  Mallika Singh,et al.  Abstract 4172: Activation of AR signaling by mifepristone enhances prostate cancer growth and impairs enzalutamide response , 2017 .

[5]  K. Tao,et al.  Fangchinoline suppresses growth and metastasis of melanoma cells by inhibiting the phosphorylation of FAK , 2017, Oncology reports.

[6]  Baoxin Wang,et al.  AGO2 involves the malignant phenotypes and FAK/PI3K/AKT signaling pathway in hypopharyngeal-derived FaDu cells , 2017, Oncotarget.

[7]  L. Salamonsen,et al.  The significance of post-translational removal of α-DG-N in early stage endometrial cancer development , 2017, Oncotarget.

[8]  Tala,et al.  Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation , 2017, Cell Discovery.

[9]  Liu Cao,et al.  miR-135a inhibits tumor metastasis and angiogenesis by targeting FAK pathway , 2017, Oncotarget.

[10]  Youzhong Zhang,et al.  Different dosages of mifepristone versus enantone to treat uterine fibroids , 2017, Medicine.

[11]  Pei-Feng Li,et al.  Understanding cardiomyocyte proliferation: an insight into cell cycle activity , 2017, Cellular and Molecular Life Sciences.

[12]  Wenjie Miao,et al.  MiR-132 plays an oncogenic role in laryngeal squamous cell carcinoma by targeting FOXO1 and activating the PI3K/AKT pathway. , 2016, European journal of pharmacology.

[13]  Florian Lang,et al.  LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a , 2016, Cellular Physiology and Biochemistry.

[14]  L. Yan,et al.  [Mifepristone inhibites the migration of endometrial cancer cells through regulating H19 methylation]. , 2016, Zhonghua zhong liu za zhi [Chinese journal of oncology].

[15]  J. Check,et al.  The progesterone receptor antagonist mifepristone does not lower serum progesterone induced blocking factor (PIBF) in the presence of progesterone. , 2016, Clinical and experimental obstetrics & gynecology.

[16]  E. Polley,et al.  New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. , 2016, Cancer treatment reviews.

[17]  Chao Dong,et al.  Mifepristone Suppresses Basal Triple-Negative Breast Cancer Stem Cells by Down-regulating KLF5 Expression , 2016, Theranostics.

[18]  F. Maquart,et al.  The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction , 2015, Oncotarget.

[19]  Zhenggang Zhu,et al.  Upregulation of long non-coding RNA LINC00152 by SP1 contributes to gallbladder cancer cell growth and tumor metastasis via PI3K/AKT pathway. , 2016, American journal of translational research.

[20]  D. McDonald,et al.  Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors , 2015, Clinical & Experimental Metastasis.

[21]  J. Jiménez-López,et al.  Tumor recurrence and tumor-related mortality in endometrial cancer: Analysis in 276 patients. , 2015, Indian journal of cancer.

[22]  Zhongmei Zhou,et al.  Abstract 4967: The BAP1 deubiquitinase promotes triple-negative breast cancer partially by stabilizing the KLF5 transcription factor , 2015 .

[23]  J. Kotwica,et al.  Onapristone (ZK299) and mifepristone (RU486) regulate the messenger RNA and protein expression levels of the progesterone receptor isoforms A and B in the bovine endometrium. , 2015, Theriogenology.

[24]  Yaoping Li,et al.  Overexpressed GRP78 affects EMT and cell-matrix adhesion via autocrine TGF-β/Smad2/3 signaling. , 2015, The international journal of biochemistry & cell biology.

[25]  C. Peng,et al.  MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial-to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2. , 2015, Toxicology letters.

[26]  M. Gilliam,et al.  Promoting community-based lifestyle modification and weight management in African American endometrial cancer survivors and their female social network , 2015 .

[27]  D. Schlaepfer,et al.  FAK activity protects nucleostemin in facilitating breast cancer spheroid and tumor growth , 2015, Breast Cancer Research.

[28]  L. Havel,et al.  FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells , 2015, Oncotarget.

[29]  Yang Song,et al.  Inositol hexaphosphate suppresses growth and induces apoptosis in HT-29 colorectal cancer cells in culture: PI3K/Akt pathway as a potential target. , 2015, International journal of clinical and experimental pathology.

[30]  Nicolas Wentzensen,et al.  Metabolic Syndrome and Risk of Endometrial Cancer in the United States: A Study in the SEER–Medicare Linked Database , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[31]  L. Ylagan,et al.  The Prognostic Significance of Focal Adhesion Kinase Expression in Stage I Non–Small-Cell Lung Cancer , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[32]  J. Settleman,et al.  Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition , 2014, Oncotarget.

[33]  M. Sarumi,et al.  Mifepristone causing complete remission of rapidly advancing leukemia with measurement of progesterone-induced blocking factor. , 2014, Anticancer research.

[34]  T. Deramaudt,et al.  Altering FAK-Paxillin Interactions Reduces Adhesion, Migration and Invasion Processes , 2014, PloS one.

[35]  J. Duan,et al.  Mechanism of the reversal effect of mifepristone on drug resistance of the human cervical cancer cell line HeLa/MMC. , 2014, Genetics and molecular research : GMR.

[36]  H. Kato,et al.  In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated β1 integrin and induction of FAK/PI3K/Akt motility signaling , 2014, Oncogene.

[37]  I. Vergote,et al.  Regional differences in therapy and clinical management of endometrial cancer: Findings of an international survey by the North-eastern German Society of Gynaecological Oncology (NOGGO). , 2013 .

[38]  Jeongmin Lee,et al.  I3C and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells. , 2013, Molecular medicine reports.

[39]  R. Vallenas Campos,et al.  Treatment of uterine myoma with 5 or 10mg mifepristone daily during 6 months, post-treatment evolution over 12 months: double-blind randomised clinical trial. , 2012, European journal of obstetrics, gynecology, and reproductive biology.

[40]  A. Riverón,et al.  Mifepristone 2.5 mg versus 5 mg daily in the treatment of leiomyoma before surgery , 2012, International journal of women's health.

[41]  L. Nieman,et al.  Mifepristone effects on tumor somatostatin receptor expression in two patients with Cushing's syndrome due to ectopic adrenocorticotropin secretion. , 2012, The Journal of clinical endocrinology and metabolism.

[42]  W. Le,et al.  Mifepristone‐Inducible Caspase‐1 Expression in Mouse Embryonic Stem Cells Eliminates Tumor Formation but Spares Differentiated Cells In Vitro and In Vivo , 2012, Stem cells.

[43]  Emma E Vincent,et al.  Akt signalling in health and disease. , 2011, Cellular signalling.

[44]  J. Guan,et al.  Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. , 2011, Advanced drug delivery reviews.

[45]  A. Molinolo,et al.  Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia. , 2010, Medicina.

[46]  P. Garcia-Lopez,et al.  Synergistic effects of mifepristone on the cytotoxicity of cisplatin in cervical carcinoma cell lines and tumors grown in athymic mice , 2007, BMC Cancer.

[47]  A. Leminen,et al.  Advanced cervical pregnancy: uterus‐sparing therapy initiated with a combination of methotrexate and mifepristone followed by evacuation and local hemostatic measures , 2004, Acta obstetricia et gynecologica Scandinavica.

[48]  S. Weed,et al.  Focal Adhesion Kinase: a regulator of focal adhesion dynamics and cell movement , 2000, Oncogene.

[49]  C. Cohen,et al.  Endometrial cancer. Management of high risk and recurrence including the tamoxifen controversy , 1995, Cancer.