Human Peritoneal Mesothelial Cells Are More Potent Than Ovarian Cancer Cells in Producing Tumor Marker CA-125

Abstract Background Ovarian cancer is a devastating gynecological malignancy and frequently presents as an advanced carcinoma with disseminated peritoneum metastasis. Acacetin exerts anti-cancerous effects in several carcinomas. Here, we sought to investigate acacetin function in ovarian cancer malignancy triggered by peritoneal mesothelial cells. Methods Peritoneal mesothelial cells were treated with acacetin, and then the conditioned medium was collected to treat ovarian cancer cells. Then, cell proliferation was analyzed by MTT assay. Transwell analysis was conducted to evaluate cell invasion. Protein expression was determined by western blotting. ELISA and qRT-PCR were applied to analyze inflammatory cytokine levels. The underlying mechanism was also explored. Results Acacetin suppressed cell proliferation and invasion, but enhanced cell apoptosis. Furthermore, mesothelial cell-evoked malignant characteristics were inhibited when mesothelial cells were pre-treated with acacetin via restraining cell proliferation and invasion, concomitant with decreases in proliferation-related PCNA, MMP-2 and MMP-9 levels. Simultaneously, acacetin reduced mesothelial cell-induced transcripts and production of pro-inflammatory cytokine IL-6 and IL-8 in ovarian cancer cells. Mechanically, acacetin decreased lysophosphatidic acid (LPA) release from mesothelial cells, and subsequent activation of receptor for advanced glycation end-products (RAGE)-PI3K/AKT signaling in ovarian cancer cells. Notably, exogenous LPA restored the above pathway, and offset the efficacy of acacetin against mesothelial cell-evoked malignancy in ovarian cancer cells, including cell proliferation, invasion and inflammatory cytokine production. Conclusions Acacetin may not only engender direct inhibition of ovarian cancer cell malignancy, but also antagonize mesothelial cell-evoked malignancy by blocking LPA release-activated RAGE-PI3K/AKT signaling. Thus, these findings provide supporting evidence for a promising therapeutic agent against ovarian cancer. Graphical Abstract

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Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

Scientific Reports ◽

10.1038/s41598-021-82686-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marina Stasenko ◽

Evan Smith ◽

Oladapo Yeku ◽

Kay J. Park ◽

Ian Laster ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Therapeutics ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Carbohydrate Binding ◽

Matrigel Invasion ◽

Galectin 3

AbstractThe lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

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CA 125 Production and Release by Ovarian Cancer Cells In Vitro

The International Journal of Biological Markers ◽

10.1177/172460089801300405 ◽

1998 ◽

Vol 13 (4) ◽

pp. 200-206 ◽

Cited By ~ 17

Author(s):

E.P. Beck ◽

A. Moldenhauer ◽

E. Merkle ◽

F. Kiesewetter ◽

W. Jäger ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Tumor ◽

Cellular Growth ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Cell Cycle Distribution ◽

Cycle Arrest

The antigenic determinant CA 125 is a high molecular weight glycoprotein which is elevated in more than 80% of patients with epithelial ovarian cancer. Despite its good performance as a human tumor marker, only little is known about its physiological function. According to recent publications, CA 125 production and release appear to be related to cellular growth. In order to investigate this putative relationship more closely, we analyzed the pattern of CA 125 production and release by ovarian cancer cells during exponential cell growth, during cell cycle arrest by colchicine and during inhibition of cellular protein synthesis by cycloheximide. The results were correlated with the cell cycle distribution. According to our results, the main determinant of CA 125 release into the culture supernatant is the total cell count. Although cell cycle arrest in the G2 + M phase by means of colchicine treatment resulted in the death of most cells, which was reflected by an increased release of CA 125, no differences in the intracellular production rate between colchicine treated and untreated cells were seen. In contrast, treatment of cells with cycloheximide not only resulted in decreasing cell numbers but also in a complete inhibition of CA 125 production by surviving cells.

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Use of L-plastin promoter to develop an adenoviral system that confers transgene expression in ovarian cancer cells but not in normal mesothelial cells

Cancer Gene Therapy ◽

10.1038/sj.cgt.7700017 ◽

1999 ◽

Vol 6 (2) ◽

pp. 99-106 ◽

Cited By ~ 35

Author(s):

Injae Chung ◽

Peter E Schwartz ◽

Ronald G Crystal ◽

Giuseppe Pizzorno ◽

John Leavitt ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Transgene Expression ◽

Mesothelial Cells ◽

Ovarian Cancer Cells

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An amplified comparative fluorescence resonance energy transfer immunosensing of CA125 tumor marker and ovarian cancer cells using green and economic carbon dots for bio-applications in labeling, imaging and sensing

Biosensors and Bioelectronics ◽

10.1016/j.bios.2017.05.003 ◽

2017 ◽

Vol 96 ◽

pp. 308-316 ◽

Cited By ~ 83

Author(s):

Somayeh Hamd-Ghadareh ◽

Abdollah Salimi ◽

Fardin Fathi ◽

Saman Bahrami

Keyword(s):

Ovarian Cancer ◽

Energy Transfer ◽

Tumor Marker ◽

Cancer Cells ◽

Fluorescence Resonance Energy Transfer ◽

Carbon Dots ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Ovarian Cancer Cells ◽

Fluorescence Resonance

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Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium

Biological Chemistry ◽

10.1515/hsz-2014-0155 ◽

2014 ◽

Vol 395 (10) ◽

pp. 1221-1231 ◽

Cited By ~ 18

Author(s):

Lana Bruney ◽

Kaitlynn C. Conley ◽

Natalie M. Moss ◽

Yueying Liu ◽

M. Sharon Stack

Keyword(s):

Ovarian Cancer ◽

Matrix Metalloproteinase ◽

Cancer Cells ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Type I ◽

Ectodomain Shedding ◽

Peritoneal Tissue ◽

Catalytically Active ◽

Membrane Type

Abstract Mucin16 [MUC16/cancer antigen 125 (CA-125)], a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further, when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP, surface expression of MUC16/CA-125 was lost, whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence, decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless, meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together, these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding, reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However, proteolytic clearing of MUC16/CA-125, catalyzed by MT1-MMP, may then expose integrins for high-affinity cell binding to peritoneal tissues, thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.

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