Propofol Inhibits HeLa Cells by Impairing Autophagic Flux via AMP-Activated Protein Kinase (AMPK) Activation and Endoplasmic Reticulum Stress Regulated by Calcium

Chen, Xi; Li, Kai; Zhao, Guoqing

doi:10.12659/msm.909144

Cited by 23 publications

(17 citation statements)

References 48 publications

(54 reference statements)

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“…Propofol, a central nervous system anesthetic, is often used in surgical operations in combination with inhalational anesthetics and analgesics. in addition to its function as an anesthetic, the antitumor effects of propofol have been demonstrated in gastric, lung, cervical and breast cancer (9)(10)(11)(12). a previous study reported that propofol inhibited the invasion of ovarian cancer cells and enhanced the apoptotic effect of paclitaxel on ovarian cancer cells (13); however, the molecular mechanisms underlying these specific roles of propofol in ovarian cancer are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

Sun

Peng

et al. 2020

Mol Med Report

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ovarian cancer is a prominent disease that demonstrates high incidence rates in women and often presents multidrug resistance. Propofol has been demonstrated to suppress the malignancy of various types of human cancer; however, the underlying molecular mechanisms of propofol in ovarian cancer remain largely unknown. The present study aimed to investigate whether and how propofol inhibits proliferation and cisplatin (ddP) resistance in ovarian cancer cells. ovarian cancer cell viability was assessed by the cell counting kit-8 assay; apoptosis and cell cycle progression were determined by flow cytometry; the relative expression levels of microRNA (miR)-374a and forkhead box O1 (FOXO1) were analyzed using reverse transcription-quantitative Pcr; the binding ability of miR-374a to FOXO1 was assessed by the dual-luciferase reporter assay; cellular sensitivity to ddP was detected using the MTT assay; and finally, the protein expression levels of FOXO1, p27, and Bcl-2-like-protein 11 (Bim) were analyzed by western blotting. Propofol reduced viability, promoted apoptosis and decreased mir-374a expression levels in A2780 cells. In addition, the viability of a2780/ddP cells in the propofol + ddP treatment group was significantly inhibited, and the apoptotic rate was increased. In addition, miR-374a overexpression increased cell viability and the proportion of cells in the S phase, and decreased the proportion of cells in the G0/G1 phase. conversely, genetic knockdown of miR-374a exerted the opposite effects on cell viability and cell cycle progression. Moreover, mir-374a was demonstrated to bind to FOXO1. Propofol promoted the expression of FOXO1, p27 and Bim, induced cell cycle arrest and decreased ovarian cancer cell viability. in addition, treatment with propofol and DDP regulated FOXO1 and increased apoptosis of ovarian cancer cells. in conclusion, propofol downregulated mir-374a and modulated the FOXO1 pathway to reduce proliferation and DDP resistance in ovarian cancer cells.

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Section: Introductionmentioning

confidence: 99%

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

Sun

Peng

et al. 2020

Mol Med Report

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“…These results clearly show that AMPK is activated by metformin even in the deficiency of LKB1. Kinases other than LKB1, namely CAMKK, ATM, and TAK1 have been reported to be able to activate AMPK (Sun et al, 2007;Herrero-Martin et al, 2009;Sanli et al, 2010;Gou et al, 2013;Fogarty et al, 2016;Loubiere et al, 2017;Chen et al, 2018). LKB1 can act as a low energy sensor and acts as a negative regulator of apoptosis in normal cells (Shaw et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Rho

Byun

Kim

et al. 2021

Biomol Ther (Seoul)

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Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphateactivated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.

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“…Previous research has shown that propofol suppresses the proliferation, differentiation, and migration of neural stem cells (NSCs), and these functions are partially mediated by the calmodulin-dependent protein kinase (CaMk) II/phosphorylation of serine at amino acid position 485 (pS485)/AMPK/activating transcription factor 5 (ATF5) signaling pathway (41). Importantly, the AMPK/ mTOR signaling pathway has been found to be activated in propofol-induced autophagosome accumulation in HeLa cells (42). Medium-and long-chain triglyceride (MCT/LCT) propofol not only significantly promotes the phosphorylation of AMPK and acetyl coenzyme A carboxylase (ACC), but also reverses the free fatty acid (FFA)-induced decreased phosphorylation of AMPK and ACC (43).…”

Section: Discussionmentioning

confidence: 99%

Propofol activates AMPK to inhibit the growth of HepG2 cells in vitro and hepatocarcinogenesis in xenograft mouse tumor models by inducing autophagy

Wang

Zhou

et al. 2020

J Gastrointest Oncol

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Background: Hepatocellular carcinoma (HCC) is a fatal malignant tumor with a poor prognosis, and is the third leading cause of cancer-related deaths worldwide. This study aimed to investigate the anti-tumor effect of propofol on the proliferation, apoptosis, and cell cycle of HCC by regulating adenosine monophosphateactivated protein kinase (AMPK) in vivo and in vitro. Methods:The cell counting Kit-8 (CCK-8) assay was employed to screen the effect of propofol on HepG2 cell viability at various concentrations (0.3, 0.6, 1.2, 2.5, 5, 10, 20, 40, 80 and 160 µM). We selected propofol at concentrations of 5, 10 and 20 µM for subsequent experiments. Flow cytometry was used to examine the apoptosis and cell cycle of HCC. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure the messenger ribonucleic acid (mRNA) expression levels of proliferating cell nuclear antigen (PCNA) and survivin. Western blotting was applied to measure the protein expression levels of PCNA, survivin, cleaved caspase-3, cleaved caspase-9, p27 (Kip1), and cyclin A. The effects of propofol were evaluated by establishing a xenograft tumor model.Results: After treatment with propofol, the mRNA expression levels of PCNA and survivin were decreased compared with the 0 µM propofol (control) group. The colony formation assay showed that the colony formation rate was obviously down-regulated. Flow cytometry demonstrated that HepG2 cell apoptosis was increased. G0/G1 was enhanced compared with the control group, while G2/M was restrained. The levels of cleaved caspase-3, cleaved caspase-9, p27, phospho-AMP-activated protein kinase α1 (p-AMPKα1), phospho-mammalian target of rapamycin (p-mTOR), and phospho-Unc-51 like autophagy activating kinase 1 (p-ULK1) were notably elevated, while the levels of cyclin A were suppressed. The xenograft tumor volume declined in vivo compared with the HepG2 xenograft group. The expression levels of cell proliferation markers (PCNA) were significantly down-regulated markedly, while the expression levels of cell cycle markers (p27) were notablyup-regulated. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining showed that cell apoptosis was increased. The levels of p-AMPKα1 were also up-regulated. Conclusions: Propofol inhibits the proliferation, apoptosis, and cell cycle of HCC by regulating AMPK in vivo and in vitro.

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Propofol Inhibits HeLa Cells by Impairing Autophagic Flux via AMP-Activated Protein Kinase (AMPK) Activation and Endoplasmic Reticulum Stress Regulated by Calcium

Cited by 23 publications

References 48 publications

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Propofol activates AMPK to inhibit the growth of HepG2 cells in vitro and hepatocarcinogenesis in xenograft mouse tumor models by inducing autophagy

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