Format

Send to

Choose Destination
J Exp Clin Cancer Res. 2019 Jan 15;38(1):19. doi: 10.1186/s13046-018-1010-1.

Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis.

Ning Y1,2, Feng W2, Cao X3,4, Ren K3,4, Quan M3,4, Chen A3,4, Xu C3,4, Qiu Y3,4, Cao J5,6, Li X7,8,9, Luo X10.

Author information

1
Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
2
The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China.
3
Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China.
4
Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China.
5
Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China. Caojianguo2005@126.com.
6
Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China. Caojianguo2005@126.com.
7
Department of preclinical medicine, Medical College, Hunan Normal University, Changsha, 410013, China. lx58616@163.com.
8
Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013, China. lx58616@163.com.
9
Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China. lx58616@163.com.
10
The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China. tluox@126.com.

Abstract

BACKGROUND:

Recent studies showed that macrophages co-cultured with ovarian cancer stem-like cells (OCSLCs) induced SKOV3 cell stemness via IL-8/STAT3 signaling. Genistein (GEN) demonstrates chemopreventive activity in inflammation-associated cancers. The present study aimed to examine whether and if GEN inhibits the stemness of SKOV3 and OVCA-3R cells induced by co-culture of THP-1 macrophages and SKOV3-derived OCSLCs.

METHODS:

The co-culture was treated with or without different concentrations (10, 20, and 40 μmol/L) of GEN for 24 h. Depletion or addition of IL-8 in Co-CM and knockdown or overexpression of STAT3 in THP-1 macrophages was performed to demonstrate the possible associated mechanisms. The combined effects of GEN and STAT3 knockdown were examined with the nude mouse modle by co-injection of SKOV3-derived OCSLCs with THP-1 macrophages.

RESULTS:

Our results showed that GEN down-regulated CD163 and p-STAT3 expression of THP-1 macrophage, decreased the levels of IL-10, increased the levels of IL-12 and nitric oxide (NO) in the conditioned medium, and reduced the clonogenic and sphere-forming capacities and the expression of CD133 and CD44 in SKOV3 cells induced by co-culture of THP-1 macrophages and OCSLCs in a dose-dependent manner. Moreover, depletion or addition of IL-8 enhanced or attenuated the effect of GEN. Additionally, knockdown or overepression of STAT3 in THP-1 macrophages potentiated or attenuated the inhibitory effects of GEN. Importantly, STAT3 overexpression retrieved the effects of IL-8 combined with GEN depletion on M2 polarization of THP-1 macrophages and stemness of SKOV3 cells induced by co-culture. The combination of GEN and STAT3 knockdown cooperatively inhibited the growth of tumors co-inoculated with OCSLCs/THP-1 macrophages in nude mice in vivo through blocking IL-8/STAT3 signaling.

CONCLUSIONS:

In summary, our findings suggested that GEN can inhibit the increased M2 polarization of macrophages and stemness of ovarian cancer cells by co-culture of macrophages with OCSLCs through disrupting IL-8/STAT3 signaling axis. This assisted GEN to be as a potential chemotherapeutic agent in human ovarian cancer.

KEYWORDS:

Genistein; IL-8/STAT3 axis; Ovarian cancer; Ovarian cancer stem-like cells; Tumor associated macrophages

PMID:
30646963
PMCID:
PMC6334437
DOI:
10.1186/s13046-018-1010-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center