Sage Journals: Discover world-class research

Abstract

Background

The abnormal expression of metastasis-associated gene 1 (MTA1) is related to the proliferation of tumor cells. Curcumin lipid nanoemulsion can effectively inhibit the growth of cervical cancer cells.

Objectives

This study mainly explores whether curcumin lipid nanoemulsion can inhibit the disease process of cervical cancer by regulating MTA1.

Materials and Methods

20 µmol/L curcumin lipid nanoemulsion was used to intervene with Hela cells for 0, 6, 12, and 24 h, respectively. Observe cell proliferation and cycle after curcumin intervention at different concentrations and at different times, observe the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway factors, and verify that PI3K is the direct target of MTA1.

Results

Curcumin lipid nanoemulsion dose-dependently inhibited cell proliferation with a more obvious at 10 µmol/L (p < 0.01). From 24 h onwards, cell number in the S phase in 20 µmol/L curcumin lipid nanoemulsion began to decrease significantly; cell number increased significantly in the G₀/G₁ phase and decreased in the G₂/M phase (p < 0.05). The higher the concentration of curcumin lipid nanoemulsion, the higher the expression of the MTA1 inhibitor, showing a certain concentration and dose dependence. MTA1 can directly target PI3K. When the concentration of curcumin lipid nanoemulsion was 10 µmol/L, the expressions of PI3K, p-AKT, and p-mTOR decreased, and the decrease was more significant at 20 µmol/L (p < 0.01).

Conclusion

Curcumin lipid nanoemulsion can inhibit cervical cancer cell proliferation and control cell growth. Curcumin lipid nanoemulsion mainly acts through the MTA1/PI3K/Akt/mTOR axis. MTA1 negatively regulates the PI3K/Akt/mTOR pathway.

Keywords

Cervical cancer curcumin lipid nanoemulsion metastasis-associated gene 1 phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway

Introduction

Curcumin is a common active compound (Yang, Han et al., 2021). Modern medical research shows that it mainly has anti-inflammatory and anti-hyperlipidemia functions. Curcumin drugs have anti-cancer effects (Yuan et al., 2022; Zheng et al., 2022), but the mechanism of their anti-cancer effects is still unclear. According to the study (Chang et al., 2021), curcumin mainly exerts anti-cancer effects through the following pathways, such as inhibiting deoxyribonucleic acid (DNA) methyltransferase; it can also modify histones; it can also regulate immune regulation, anti-oxidation, and interfering with hormone levels, and so on, pathways to exert anti-tumor effects. In addition, there are also studies that (Mahmoudi et al., 2022; Maleki Dizaj et al., 2022; Tiwari et al., 2014), curcumin drugs can regulate the expression of intracellular miRNA, control cell growth, and finally play an anti-cancer role.

Metastasis-associated gene 1 (MTA1) was identified in highly metastatic breast adenocarcinoma cells (Jia et al., 2019). Previous data have shown that MTA1 can act as a co-activator of the complex by interacting with histone deacetylases. Overexpression of MTA1 is related to the activities of some cancer cells (Guo et al., 2019), and it is found in many malignant tumor types. Among them, MTA1 overexpression was associated with higher tumor grade and poor prognosis (He et al., 2014). In cervical cancer cells, the MTA1 gene is abnormally expressed, and it is further found that MTA1 can act as a tumor suppressor gene, and its tumor suppressor mechanism is still unclear. Nicolson et al. (2003) found that the expression of MTA1 in cervical cancer was decreased. All the above studies indicated that the abnormal expression of MTA1 may be related to the progression of cervical cancer. However, the specific mechanism of action of MTA1 in cervical cancer remains unclear.

Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) is related to the progression of various tumor diseases and can participate in tumor cell proliferation. It shows that the PI3K/Akt/mTOR pathway may be linked to cervical cancer proliferation and cell cycle (Bossler et al., 2019; Sun et al., 2020; Zhang et al., 2021). MTA1 mediates the PI3K/Akt/mTOR pathway and regulates the biological behavior of tumor cells (Chen et al., 2022). Zhang et al. (2022) found that MTA1 can inhibit the activity of the PI3K/Akt/mTOR pathway and control the growth of cervical cancer cells. In our previous experiment (Wang et al., 2020), by constructing a mouse model of cervical cancer, the research results found that after curcumin drug intervention, MTA1 expression in cervical cancer tissue was increased. This preliminarily suggests that curcumin drugs may play an anti-cancer therapeutic role by promoting the expression of MTA1.

In addition, if curcumin drugs are directly used to intervene with cells, there may be instability, and the drug concentration will also be affected. Based on the advantages of improving drug stability and ensuring drug concentration, this study prepared curcumin lipid nanoemulsions, which are used to intervene in cervical cancer cells to ensure drug stability, and so on. This study analyzed the level of cell experiments to clarify further whether MTA1 can be used as a drug target for cervical cancer. At the same time, it is hoped that this study can further explain the potential mechanism of action of curcumin lipid nanoparticles in treating cervical cancer and provide a new direction for future research. The schematic diagram of the mechanism is shown in Figure 1.

Figure 1.

Note: MTA1, metastasis-associated gene 1.

Materials and Methods

Experimental Reagents and Instruments

Cervical cancer cell Hela (Biometrics); primary anti-body (PI3K, AKT, p-AKT, mTOR, p-mTOR, 1:500; GAPDH, 1:1,000) (Abcam); secondary anti-body (Santa Cruz); Fetal bovine serum, penicillin, streptomycin (Costar); Lipofectamine™ 2000 kit, flow cytometer, electrophoresis tank (Merck); transmission electron microscope, particle analyzer (Zhuhai Omega).

Research Methods

Preparation of Curcumin Lipid Nanoemulsion

First, prepare the oil phase: mix palm oil, curcumin, and absolute ethanol. Add the oil to the water phase to form colostrum, homogenize for 10 min, and obtain curcumin lipid nanoemulsion. Take an appropriate amount of curcumin lipid nanoemulsion, deionized water, ultrasonic dispersion, take a proper amount of liquid sample dropwise onto the copper mesh, absorb the excess liquid with filter paper, dry it in the sun, put it into an electron microscope to observe the shape, and then use a particle analyzer to detect the size of granule. The synthetic diagram of the preparation is shown in Figure 2.

Figure 2.

Schematic Diagram of Nanomaterial Synthesis.

Cell Intervention

Cell Culture

Cervical cancer cells were purchased from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and cultured in a Dulbecco’s Modified Eagle Medium (DMEM) medium.

Cell Transfection

According to the instructions of the kit, the negative control and the inhibitory tumor cells that down-regulate its expression were transfected, respectively. Cells were cultured and grouped as described above. Transient transfection was used. Liposomes and 20 nM negative control were mixed for transfection. After 48 h of action, a standard culture medium was used for culture.

Cell Intervention

Different concentrations (0, 10, and 20 µmol/L) of curcumin NPs were added to Hela cells (1 × 10⁴/mL and 1 × 10⁸/mL). Alternatively, 20 µmol/L curcumin lipid nanoemulsion was used to intervene in Hela cells, and the intervention time was 0, 6, 12, and 24 h, respectively. Or use 20 µmol/L curcumin lipid nanoemulsion to intervene Hela cells that have been transfected with MTA1 inhibitor.

Cell Biological Behavior Observation

5-Ethynyl-2′-Deoxyuridine (EDU) Staining

Take the above cells Hela, inoculate, add EDU reagent at the following time points (0, 5, 10, 15, 20 h), culture, wash with phosphate-buffered saline (PBS), fix, add Apollo solution, incubate, wash with PBS, stain with 4′,6-diamidino-2-phenylindole (DAPI), and count.

Cell Cycle

Take the above-mentioned HeLa cells after successful transfection, wash with PBS, centrifuge at 1,000 r/min for 5 min, make a single cell suspension, add Annenin V-PE, 7-AAD, incubate for 15 min, add 70% ethanol solution, dose 1 mL, and machine detects the cell cycle.

RT-PCR

Ribonucleic acid (RNA) was isolated for complementary deoxyribonucleic acid (cDNA) synthesis followed by reverse transcription polymerase chain reaction (RT-PCR) with conditions: 95°C for 5 min, 94°C for 30 s, 40 cycles, 72°C for 10 min, 35 cycles. The primer sequences are listed in Table 1.

Table 1.

Primer Sequences.

Primer	Sequences		Length (bp)
MTA1	Forward	5′-GATCGAAGCTAGCAGAGAGTACTTTAG-3′	25
	Reverse	5′-GAGCTAGAGCTCGCAGAGAGTATATAT-3′
β-actin	Forward	5′-AAGAAGCACATCAGAGAGTGTTCTTGG-3′	22
	Reverse	5′-GATGAATCGTCTTGGGGCGAAATAAAC-3′

Note: MTA1, metastasis-associated gene 1.

Western Blot

Isolated protein (50 µg) was separated by gel electrophoresis and transferred to polyvinylidene fluoride (PVDF) membrane for western blot. ECL chemiluminescent reagents detect signal expression.

Dual-Luciferase Reporter Gene Experiment

Transfect MTA1 and plasmids (wild-type plasmids, mutant plasmids) into MTA1 mimics or NC plasmids, dilute, blow off, centrifuge, add working solution, and detect.

Observation Indicators

Observe the proliferation and cell cycle of Hela cells, observe the protein expression of PI3K/Akt/mTOR pathway factors simultaneously, and verify that PI3K is the direct target gene of MTA1.

Statistical Methods

Data are presented as Mean ± SD and analyzed using SPSS21.0 software. The significant difference was confirmed by a one-way analysis of variance (LSD). p < 0.05 refers to a difference.

Results

Preparation of Curcumin Lipid Nanoemulsion

The synthesized curcumin lipid nanoemulsion is shown in Figure 3A. It was analyzed by transmission electron microscopy (TEM) (Figure 3A, 1:50 nm, B, 1:100 nm, and C 1:500 nm), showing that the curcumin lipid nanoemulsion sample consisted of an average diameter (SD) of 94.1 ± 11.6 nm spherical particle composition. As shown in Figure 3D.

Figure 3.

Note: (A) Represents particle morphology (scale bar 1: 50 nm); (B) (scale bar 1: 100 nm); (C) (scale bar 1: 500 nm) represents particle size (×400); (D) represents curcumin lipid nanoemulsion. The potential distribution is normal.

Curcumin Lipid Nanoemulsion Can Reverse the Cycle and Proliferation of Cervical Cancer Cells

Curcumin lipid nanoemulsion dose-dependently inhibited cell proliferation (p < 0.01). See Figure 4A. From 24 h onwards, cell number in the S phase in 20 µmol/L curcumin lipid nanoemulsion began to decline significantly with increased number in the G₀/G₁ phase and decreased number in the G₂/M phase (p < 0.05) (Table 2). The results of flow cytometry showed that the cell proliferation in 15 µmol/L, and 20 µmol/L curcumin lipid nanoemulsion was obvious (Figure 4B and C).

Figure 4.

Note: (A) Represents fluorescent staining (scale bar = 200 µm); (B, C) represents cell cycle expression detected by flow cytometry 15 µmol/L and 20 µmol/L with curcumin lipid nanoemulsion. DAPI, 4′,6-diamidino-2-phenylindole; EDU, 5-ethynyl-2′-deoxyuridine.

Table 2.

Cell Cycle.

Curcumin Lipid Nanoemulsion Concentration	24 h			48 h			72 h
Curcumin Lipid Nanoemulsion Concentration	G₀/G₁	S	G₂/M	G₀/G₁	S	G₂/M	G₀/G₁	S	G₂/M
0 µmol/L	64.22 ± 3.88	24.34 ± 2.01	11.42 ± 1.74	66.91 ± 5.84	23.02 ± 1.91	10.08 ± 0.87	67.82 ± 4.68	21.82 ± 1.89	10.34 ± 1.24
10 µmol/L	66.99 ± 3.55^*	21.24 ± 2.42^*	11.76 ± 1.22^*	73.19 ± 3.44^*	17.56 ± l.12^*	9.21 ± 0.54^*	75.22 ± 4.15^*	17.18 ± 2.56^*	7.61 ± 1.02^*
20 µmol/L	72.78 ± 4.84^*	16.43 ± 1.53^*	10.78 ± 0.93^*	84.76 ± 6.24^*	12.11 ± 0.96^*	3.13 ± 0.22^*	85.31 ± 4.05^*	11.53 ± 2.03^*	3.17 ± 0.47^*
F	5.608	12.587	1.745	9.403	38.325	108.392	13.788	18.267	63.677
p	0.007	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001

Note: Compared with 0 µmol/L, * p < 0.05, n = 5.

Curcumin Lipid Nanoemulsion Can Promote MTA1 Expression in Cervical Cancer Cells

The higher the concentration of curcumin lipid nanoemulsion, the higher the expression of MTA1 in cervical cancer cells, showing a certain concentration and dose dependence; the longer intervention time of 20 µmol/L curcumin lipid nanoemulsion, the higher MTA1 expression in cervical cancer cells. The higher it is, the more time-dependent it is (Figure 5A, B). Flavolipid nanoemulsions of 15 µmol/L and 20 µmol/L had consistent effects on cell proliferation and cycle, and 20 µmol/L was used for subsequent intervention. The results of cell scratching showed that under the intervention of 20 µmol/L concentration, the cell motility was weakened, as shown in Figure 5C.

Figure 5.

Notes: (A) Shows the expression of MTA1 under different curcumin lipid nanoemulsion concentration conditions, (B) shows the expression of MTA1 under different time conditions, and (C) shows the expression of cell motility (scale bar = 200 µm). Compared with 0 µmol/L, *p < 0.05, **p < 0.01, ***p < 0.001. MTA1, metastasis-associated gene 1.

PI3K is the Direct Target Gene of MTA1

After analysis by Targetscan software, there is a specific binding region between the MTA1 sequence and the 3′-UTR 545-565 sequence of the PI3K gene, and PI3K is the target gene of MTA1 (Figure 6A). The fluorescence intensity of the mutant plasmid was higher than the wild-type plasmid (p < 0.05) (Figure 6B). When the concentration of curcumin lipid nanoemulsion was 10 µmol/L, the protein expressions of PI3K, p-AKT, and p-mTOR all decreased significantly, and the decrease was more significant at 20 µmol/L (p < 0.01). In addition, when comparing different concentrations of AKT and mTOR, p > 0.05 (Table 3 and Figure 6C).

Figure 6.

Notes: (A) Shows Targetscan software analysis, (B) shows luciferase activity analysis, (C) shows western-blot detection analysis. Compared with PI3K, *p < 0.05. Akt, protein kinase B; MTA1, metastasis-associated gene 1; mTOR, mammalian target of rapamycin; ns, no statistical; PI3K, phosphoinositide 3-kinase.

Table 3.

Protein Expression of PI3K/Akt/mTOR Pathway Factors.

Curcumin Lipid Nanoemulsion Concentration	PI3K	AKT	p-AKT	mTOR	p-mTOR
0 µmol/L	1.99 ± 0.55	1.28 ± 0.02	1.36 ± 0.04	1.89 ± 0.44	1.56 ± 0.02^*
10 µmol/L	0.32 ± 0.06^*	1.34 ± 0.03	0.42 ± 0.03^*	1.91 ± 0.52	0.22 ± 0.01^*
20 µmol/L	0.22 ± 0.08^**	1.32 ± 0.03	0.31 ± 0.04^**	1.81 ± 0.54	0.12 ± 0.03^**
F	7.121	1.500	41.505	0.257	89.305
P	0.000	0.172	0.000	0.804	0.000

Notes: Compared with 0 µmol/L, *p < 0.05, n = 5. Akt, protein kinase B; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.

Discussion

To improve the stability of the curcumin drug and its concentration without interference, this study successfully prepared curcumin lipid nanoemulsion to interfere with cervical cancer cells. First, observe the proliferation and cell cycle changes of cervical cancer cells. Our results found that when the concentration of curcumin lipid nanoemulsion is 10 µmol/L, cells number in the S phase and G₂/M phase is significantly reduced. The results show that curcumin lipid nanoemulsion, can interfere with the cell cycle, thereby inhibiting the cell proliferation process and finally controlling the abnormal growth of cervical cancer cells, thereby exerting an anti-cancer therapeutic effect. The results of the study found that curcumin lipid nanoemulsion drugs can promote apoptosis of cervical cancer cells and play a therapeutic role, both of which indicate that curcumin lipid nanoemulsion drugs can exert an anti-cancer effect on cervical cancer, consistent with our results (Park et al., 2011; Rao et al., 2011; Wei et al., 2021).

Previous studies have found that curcumin lipid nanoemulsion has an anti-cancer effect on cervical cancer and abnormal changes in the expression of MTA1 (Park et al., 2011; Rao et al., 2011; Wei et al., 2021). The effect of different intervention concentrations and time on MTA1 expression in cervical cancer cells was analyzed. Our results found that with the increase of the concentration of curcumin lipid nanoemulsion, MTA1 expression also increased. In addition, it was also found that 20 µmol/L Curcumin lipid nanoemulsion for intervention. We further indicate that MTA1 expression in cervical cancer cells has a dose-dependent and time-dependent relationship with the concentration of curcumin lipid nanoemulsion and the intervention time.

Compared with the cells that interfered with curcumin lipid nanoemulsion, the research results found that after transfection with curcumin, the number of cell proliferation was also significantly reduced, but after adding MTA1 inhibitor on this basis, the cell proliferation and cell cycle changes were similar to those of On the contrary, the results of this study suggest that curcumin lipid nanoemulsion mainly inhibits cells in S phase and G₂/M phase by promoting the expression of MTA1, but the MTA1 inhibitor easily releases this, that is, after the MTA1 inhibitor is added to the cells, the curcumin lipid The nanoemulsion could not play a therapeutic role, which further indicated that curcumin lipid nanoemulsion played a role in promoting the expression of MTA1. Previous studies have shown that after MTA1 mimics interfered with cervical cancer cells (Xiao et al., 2021), cell proliferation was inhibited, but after MTA1 inhibitor was added, cell proliferation was promoted, and both groups of cells were under the premise of curcumin lipid nanoemulsion drug intervention. The MTA1 transfection operation suggested that curcumin lipid nanoemulsion may inhibit cell proliferation by promoting MTA1 expression.

To reveal the therapeutic mechanism of curcumin lipid nanoemulsion drug on MTA1. First confirmed the targeting relationship between MTA1 and PI3K (Xiao et al., 2021; Yang, Wang et al., 2021). It can induce apoptosis, and some studies have also shown that (Yin et al., 2021) Inhibiting PI3K/Akt/mTOR axis can inhibit cervical cancer cells proliferation. This study further observed the changes of PI3K/Akt/mTOR pathway factors after different concentrations of curcumin lipid nanoemulsion interfered with cervical cancer cells. With the higher concentration of curcumin lipid nanoemulsion, the PI3K, p-Akt, and p-mTOR protein decreased significantly. After the expression of PI3K decreases, cells number in the S and G₂/M phases decreases, and inhibit the proliferation of cervical cancer cells (Borah et al., 2020; Zhan et al., 2021; Zhang et al., 2016). We further indicate that MTA1 can be used as a drug target of curcumin lipid nanoemulsion to inhibit cervical cancer cells by inhibiting the activity of the PI3K/Akt/mTOR pathway.

Conclusion

Curcumin lipid nanoemulsion inhibits cell number in the S phase and G₂/M phase, causing G₀/G₁ arrest, inhibiting cervical cancer cells from entering the next cell cycle, and then controlling cell growth. Curcumin lipid, the mechanism of the therapeutic effect of nanoemulsion on cervical cancer, is related to MTA1. Curcumin mainly acts through the MTA1/PI3K/Akt/mTOR axis, and MTA1 targets PI3K to regulate cell proliferation. However, this study also has limitations. The involvement of the PI3K/Akt/mTOR pathway in cervical cancer cells needs further research. In addition to PI3K, the target genes of MTA1 include ZHX1, mTOR, and so on. Whether MTA1 affects cervical cancer cells through other target genes requires further study.

Footnotes

Abbreviations

AKT: protein kinase B; MTA1: metastasis-associated gene 1; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase.

Acknowledgments

The authors gratefully acknowledge the Ganzhou People’s Hospital Laboratory for providing the necessary equipment for this study.

The author Yanhua Yu is also affiliated with Department of Clinical Laboratory, Huangshi Love & Health Hospital, Huangshi, Hubei, China.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval and Informed Consent

This study was approved by the ethics committee of Ganzhou People’s Hospital.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Guiwei Zhong

References

Borah

, Pillai

S. C.

, Rochani

A. K.

, Palaninathan

, Nakajima

, Maekawa

, & Kumar

D. S.

(2020). GANT61 and curcumin-loaded PLGA nanoparticles for GLI1 and PI3K/Akt-mediated inhibition in breast adenocarcinoma. Nanotechnology , 31(18), 185102. https://doi.org/10.1088/1361-6528/ab6d20

Bossler

, Hoppe-Seyler

, & Hoppe-Seyler

(2019). PI3K/AKT/mTOR signaling regulates the virus/host cell crosstalk in HPV-positive cervical cancer cells. International Journal of Molecular Sciences , 20(9), 2188. https://doi.org/10.3390/ijms20092188

Chang

L. S.

, Zhang

Y. H.

, Li

, Zhao

X. J.

, Wang

D. L.

, Liu

, Zhou

, & Zhang

(2021). Nanostructured lipid carrier co-delivering paclitaxel and doxorubicin restrains the proliferation and promotes apoptosis of glioma stem cells via regulating PI3K/Akt/mTOR signaling. Nanotechnology , 32(22), 225101. https://doi.org/10.1088/1361-6528/abd439

Chen

L. Y.

, Qing

J. L.

, Xiao

Y. Y.

, Huang

X. M.

, Chi

Y. L.

, & Chen

Z. Z.

(2022). TIM-1 promotes proliferation and metastasis, and inhibits apoptosis, in cervical cancer through the PI3K/AKT/p53 pathway. BMC Cancer , 22(1), 370. https://doi.org/10.1186/s12885-022-09386-7

Guo

, Shen

, Zhang

, Moustafa

A. A.

, Ge

D. X.

, & You

Z. B.

(2019). Interleukin-17 promotes migration and invasion of human cancer cells through upregulation of MTA1 expression. Frontiers in Oncology , 9, 546. https://doi.org/10.3389/fonc.2019.00546

, Zhou

, Zheng

, & Xiong

(2014). Overexpression of MTA1 promotes invasiveness and metastasis of ovarian cancer cells. Irish Journal of Medical Science , 183(3), 433–438. https://doi.org/10.1007/s11845-013-1034-7

Jia

Q.-P.

, Yan

C.-Y.

, Zheng

X.-R.

, Pan

, Cao

, & Cao

(2019). Upregulation of MTA1 expression by human papillomavirus infection promotes CDDP resistance in cervical cancer cells via modulation of NF-B/APOBEC3B cascade. Cancer Chemotherapy and Pharmacology , 83(4), 625–637. https://doi.org/10.1007/s00280-018-03766-2

Mahmoudi

, Kesharwani

, Majeed

, Teng

, & Sahebkar

(2022). Recent advances in nanogold as a promising nanocarrier for curcumin delivery. Colloids and Surfaces. B, Biointerfaces , 215, 112481. https://doi.org/10.1016/j.colsurfb.2022.112481

Maleki Dizaj

, Alipour

, Dalir Abdolahinia

, Ahmadian

, Eftekhari

, Forouhandeh

, Rahbar Saadat

, Sharifi

, & Zununi Vahed

(2022). Curcumin nanoformulations: Beneficial nanomedicine against cancer. Phytotherapy Research , 36(3), 1156–1181. https://doi.org/10.1002/ptr.7389

10.

Nicolson

G. L.

, Nawa

, Toh

, Taniguchi

, Nishimori

, & Moustafa

(2003). Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: Role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clinical and Experimental Metastasis , 20(1), 19–24. https://doi.org/10.1023/a:1022534217769

11.

Park

J.-O.

, Jung

C.-K.

, Sun

D.-I.

, Joo

Y.-H.

, & Kim

M.-S.

(2011). Relationships between metastasis-associated protein (MTA) 1 and lymphatic metastasis in tonsil cancer. European Archives of Oto-Rhino-Laryngology , 268(9), 1329–1334. https://doi.org/10.1007/s00405-010-1478-6

12.

Rao

Y. M.

, Wang

H. Y.

, Fan

L. S.

, & Chen

(2011). Silencing MTA1 by RNAi reverses adhesion, migration and invasiveness of cervical cancer cells (SiHa) via altered expression of p53, and E-cadherin/beta-catenin complex. Journal of Huazhong University of Science and Technology (Medical Science) , 31(1), 1–9. https://doi.org/10.1007/s11596-011-0141-9

13.

Sun

, Luo

, Guo

, Yao

, Jing

, & Guo

(2020). The PI3K/AKT/mTOR signaling pathway in osteoarthritis: A narrative review. Osteoarthritis and Cartilage , 28(4), 400–409. https://doi.org/10.1016/j.joca.2020.02.027

14.

Tiwari

S. K.

, Agarwal

, Seth

, Yadav

, Nair

, Bhatnagar

, Karmakar

, Kumari

, Chauhan

L. K. S.

, Patel

D. K.

, Srivastava

, Singh

, Gupta

S. K.

, Tripathi

, Chaturvedi

R. K.

, & Gupta

K. C.

(2014). Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/beta-catenin pathway. ACS Nano , 8(1), 76–103. https://doi.org/10.1021/nn405077y

15.

Wang

A. H.

, Zhao

J. M.

, Du

, Pang

Q. X.

, & Wang

M. Q.

(2020). Long noncoding RNA LUCAT1 promotes cervical cancer cell proliferation and invasion by upregulating MTA1. European Review for Medical and Pharmacological Sciences , 24(17), 8623–8623. https://doi.org/10.26355/eurrev_202009_22750

16.

Wei

J. H.

, Zhang

X. F.

, Pan

H. H.

, He

, Yuan

, Liu

, Zhang

, & Ding

(2021). Eupafolin inhibits breast cancer cell proliferation and induces apoptosis by inhibiting the PI3K/Akt/mTOR pathway. Oncology Letters , 21(4), 332. https://doi.org/10.3892/ol.2021.12593

17.

Xiao

, Lin

C. H.

, Yang

Z. X.

, Tian

S. H.

, Huang

Y. A.

, & Fu

(2021). Compound TDB (tricyclic decyl benzoxazole) induces autophagy-dependent apoptosis in the gastric cancer cell line MGC-803 by regulating PI3K/AKT/mTOR. American Journal of Translational Research , 13(1), 73–87.

18.

Yang

, Han

M. M.

, Li

R. Y.

, Zhou

L. G.

, Zhang

, Duan

L. N.

, Su

, Li

, Wang

, Chen

, & Mo

Y. S.

(2021). Curcumin nanoparticles inhibiting ferroptosis for the enhanced treatment of intracerebral hemorrhage. International Journal of Nanomedicine , 16, 8049–8065. https://doi.org/10.2147/IJN.S334965

19.

Yang

, Wang

, Zhang

G. H.

, Li

Y. P.

, Wang

L. L.

, & Cui

H. J.

(2021). POU2F2 regulates glycolytic reprogramming and glioblastoma progression via PDPK1-dependent activation of PI3K/AKT/mTOR pathway. Cell Death and Disease , 12(5), 433. https://doi.org/10.1038/s41419-021-03719-3

20.

Yin

Z. X.

, Yang

Y. N.

, Guo

T. F.

, Veeraraghavan

V. P.

, & Wang

(2021). Potential chemotherapeutic effect of betalain against human non-small cell lung cancer through PI3K/Akt/mTOR signaling pathway. Environmental Toxicology , 36(6), 1011–1020. https://doi.org/10.1002/tox.23100

21.

Yuan

R. Y. K.

, Li

Y. Q.

, Han

, Chen

X. X.

, Chen

J. Q.

, He

, Gao

, Yang

, & Yang

(2022). Fe-curcumin nanozyme-mediated reactive oxygen species scavenging and anti-inflammation for acute lung injury. ACS Central Science , 8(1), 10–21. https://doi.org/10.1021/acscentsci.1c00866

22.

Zhan

D. L.

, Lin

M. X.

, Chen

, Cai

W. T.

, Liu

, Fang

Y. H.

, Li

, Wu

, & Wang

G. J.

(2021). Hypoxia-inducible factor-1 alpha regulates PI3K/AKT signaling through microRNA-32-5p/PTEN and affects nucleus pulposus cell proliferation and apoptosis. Experimental and Therapeutic Medicine , 21(6), 646. https://doi.org/10.3892/etm.2021.10078

23.

Zhang

H. X.

, Zhu

Y. J.

, Sun

X. Y.

, He

X. L.

, Wang

Z. Q.

, Wang

, Zhu

, & Wang

S. L.

(2016). Curcumin-loaded layered double hydroxide nanoparticles-induced autophagy for reducing glioma cell migration and invasion. Journal of Biomedical Nanotechnology , 12(11), 2051–2062. https://doi.org/10.1166/jbn.2016.2291

24.

Zhang

H.-Q.

, Xie

X.-F.

, Li

G.-M.

, Chen

J.-R.

, Li

M.-T.

, Xu

, Xiong

Q.-Y.

, Chen

G.-R.

, Yin

Y.-P.

, Peng

, Chen

, & Peng

(2021). Erianin inhibits human lung cancer cell growth via PI3K/Akt/mTOR pathway in vitro and in vivo. Phytotherapy Research , 35(8), 4511–4525. https://doi.org/10.1002/ptr.7154

25.

Zhang

L. R.

, Li

, & Zhang

L. P.

(2022). SRSF3 restriction eases cervical cancer cell viability and metastasis via adjusting PI3K/AKT/mTOR signaling pathway. Contrast Media and Molecular Imaging , 2022, 8497078. https://doi.org/10.1155/2022/8497078

26.

Zheng

Y. S.

, Jia

, Li

, Tian

X. H.

, & Qian

Y. B.

(2022). Curcumin- and resveratrol-co-loaded nanoparticles in synergistic treatment of hepatocellular carcinoma. Journal of Nanobiotechnology , 20(1), 339. https://doi.org/10.1186/s12951-022-01554-y

Curcumin Lipid Nanoemulsion Inhibits Cervical Cancer Progression by Upregulating Metastasis-associated Gene 1

Abstract

Background

Objectives

Materials and Methods

Results

Conclusion

Keywords

Introduction

Materials and Methods

Experimental Reagents and Instruments

Research Methods

Preparation of Curcumin Lipid Nanoemulsion

Schematic Diagram of Nanomaterial Synthesis.

Cell Intervention

Cell Culture

Cell Transfection

Cell Intervention

Cell Biological Behavior Observation

5-Ethynyl-2′-Deoxyuridine (EDU) Staining

Cell Cycle

RT-PCR

Primer Sequences.

Western Blot

Dual-Luciferase Reporter Gene Experiment

Observation Indicators

Statistical Methods

Results

Preparation of Curcumin Lipid Nanoemulsion

Curcumin Lipid Nanoemulsion Can Reverse the Cycle and Proliferation of Cervical Cancer Cells

Cell Cycle.

Curcumin Lipid Nanoemulsion Can Promote MTA1 Expression in Cervical Cancer Cells

PI3K is the Direct Target Gene of MTA1

Protein Expression of PI3K/Akt/mTOR Pathway Factors.

Discussion

Conclusion

Footnotes

Abbreviations

Acknowledgments

Declaration of Conflicting Interests

Ethical Approval and Informed Consent

Funding

ORCID iD

References