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ORIGINAL ARTICLE
Year : 2012  |  Volume : 49  |  Issue : 1  |  Page : 181-187
 

In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines


1 Department of Health Foods, Interactive Research School of Health Affairs, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India
2 Department of Surgery, Bharati Hospital, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India
3 Department of Cell Repository National Center for Cell Science, Pune, Maharashtra, India

Date of Web Publication25-Jul-2012

Correspondence Address:
S S Chandorkar
Department of Surgery, Bharati Hospital, Bharati Vidyapeeth Deemed University, Pune, Maharashtra
India
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Source of Support: ICAR NAIP projects on flaxseed to Bharati Vidyapeeth Deemed University, Conflict of Interest: None


DOI: 10.4103/0019-509X.98948

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 » Abstract 

Background: Actin cytoskeleton is involved in actin-based cell adhesion, cell motility, and matrix metalloproteinases(MMPs) MMP2, MMP9, MMP11 and MMP14 are responsible for cell invasion in breast cancer metastasis. The dietary intake of lignan from flax seed gets converted to enterolactone (EL) and enterodiol in the human system. Here we show that the enterolactone has a very significant anti-metastatic activity as demonstrated by its ability to inhibit adhesion and invasion and migration in MCF-7 and MDA MB231 cell lines. Materials and Methods: Migration inhibition assay, actin-based cell motility assay along with reverse transcriptase polymerase chain reaction (RT-PCR) for MMP2, MMP9, MMP11 and MMP14 genes were performed in MCF-7 and MDA MB 231 cell lines. Results: Enterolactone seems to inhibit actin-based cell motility as evidenced by confocal imaging and photo documentation of cell migration assay. The results are supported by the observation that the enterolactone in vitro significantly down-regulates the metastasis-related metalloproteinases MMP2, MMP9 and MMP14 gene expressions. No significant alteration in the MMP11 gene expression was found. Conclusions: Therefore we suggest that the anti-metastatic activity of EL is attributed to its ability to inhibit cell adhesion, cell invasion and cell motility. EL affects normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby inhibits actin-based cell adhesion and cell motility. The process involves multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction. By down-regulating the metastasis-related MMP2, MMP9 and MMP14 gene expressions, EL may be responsible for cell invasion step of metastasis.


Keywords: Actin cytoskeleton, enterolactone, matrix metalloproteinases


How to cite this article:
Mali A V, Wagh U V, Hegde M V, Chandorkar S S, Surve S V, Patole M V. In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines. Indian J Cancer 2012;49:181-7

How to cite this URL:
Mali A V, Wagh U V, Hegde M V, Chandorkar S S, Surve S V, Patole M V. In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines. Indian J Cancer [serial online] 2012 [cited 2020 Jun 6];49:181-7. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/181/98948



 » Introduction Top


Breast cancer is one of the most common malignancies affecting developed as well as developing countries and although recent advances have been made in tumor detection and treatment, the development of clinical metastasis remains a significant cause of morbidity and mortality from the disease. [1] Metastasis is a complex multi-step process, involving: cell adhesion, invasion and motility. Hence, interruption of one or more of these steps can be an approach for anti-metastatic therapy. [2] Initial invasive action of metastatic cells involves interaction of tumor cells with the extra-cellular matrix (ECM), involving cell matrix adhesion. Once malignant cells have detached from the primary tumor, they bombard the surrounding basement membrane (BM). [3] The BM is the largest barrier between a free malignant cell and the blood stream, and it must be traversed before malignant cells can enter the circulation. [4] Therefore, invasion through a BM is a critical step in metastasis. An additional step in the process of invasion involves degradation of the BM via proteolytic enzymes. Matrix metalloproteinases (MMPs) display specific proteolytic activity against components of the ECM and their over-expression has been linked to invasiveness of breast cancer cells in vitro. [1],[5] Motility is another property of malignant cells needed to migrate from the primary site to a secondary organ. Cell locomotion is undoubtedly complex, requiring coordinated activity of cytoskeletal, membrane, and adhesion systems and actin filaments themselves are likely to be involved in multiple force-generating mechanisms. It is now widely accepted that the basic engine for gliding or crawling locomotion is the actin cytoskeleton. Any alteration in this property of actin filaments can be expected to interrupt the metastatic process. [6]

Flaxseed is an excellent source of dietary fiber, omega 3 fat (as alpha-linolenic acid), and lignan, secoisolariciresinol diglycoside (SDG), which is metabolized by bacteria in the colon to the mammalian lignans, enterodiol (ED) and enterolactone (EL). [7],[8] Intake of flaxseed, especially its lignan fraction lowers cancer risk and thus these compounds are thought to be in part responsible for the anti-cancer effect of flaxseed. [9] Some previous studies have shown that flaxseed can inhibit the spontaneous metastasis of the estrogen receptor negative (ER−) human breast cancer MDA-MB-435 in nude mice [10],[11] and the experimental lung metastasis of murine melanoma B16BL6 cells in mice, [12] and lignans and tamoxifen (TAM), alone or in combination, can inhibit the steps involved in the metastasis cascade. [2] Some cell and animal studies provide evidences that other phytoestrogens, in addition to genistein, possess chemopreventive properties as demonstrated by their ability to inhibit the invasion of the highly metastatic breast cancer cell line MDA-MB-231 through matrigel, [1] and dietary flaxseed inhibits human breast cancer growth and metastasis and down-regulates expression of insulin-like growth, epidermal growth factor [10] and vascular endothelial growth factor. [11] However, the cellular mechanism by which flaxseed and its components inhibit metastasis, that is, how they influence the individual steps in the metastatic cascade, has not yet been investigated.

Once metastases are detected by 'classical' means--clinical manifestations of the spread, imaging methods (such as tomography) and serum marker assays, such as those based on carcinoma antigen 15.3 (CA15.3) or carcino embryonic antigen (CEA), breast cancer is generally no longer curable. [13] Therefore the anti-metastatic drugs can be an effective approach to inhibit the spread of the disease to other tissues, a useful therapeutic measure in the treatment and management of cancer. We present here cellular and molecular studies that suggest the mechanism by which the dietary flaxseed lignan-derived enterolactone (EL) may inhibit the adhesion, invasion and migration processes involved in metastasis.


 » Materials and Methods Top


Compounds

Pure enterolactone (EL) was purchased from Sigma-Aldrich Canada. 4mM stock of EL was prepared by dissolving 1 mg of enterolactone in 825 μl of absolute ethanol and freshly diluted as working solutions before use. Ethanol concentrations in working solutions had no effects on the cell proliferation, adhesion, invasion and migration.

Cell culture

Human breast cancer cell line MDA MB 231, was used for the migration inhibition assay and actin-based cell motility assay. Cell line was routinely cultured in L-15 medium with 10% Fetal Bovine Serum and cells were incubated at 37 0 C without CO 2 . Two human breast cancer cell lines MCF-7 and MDA MB 231, were used for breast cancer MMPs gene expression studies. MCF-7 cell line was routinely cultured in DMEM medium with 10% Fetal Bovine Serum and cells were incubated at 37 0 C with CO 2 . Both the cell lines were passaged in 1:3 ratio after they reached the 100% confluency. Among the two cell lines, the MCF-7 cell line is estrogen-dependent while the MDA MB 231 is estrogen independent and both are known to possess metastatic potential in vivo and in vitro.

Migration inhibition assay

1 × 10 6 cells of MDA MB 231 cell line were seeded in a 6-well plate. When the cells reached to 90% confluency, a wound was prepared by scrapping off the cells using a scrapper or a tip. Detached cells were washed off and the remaining cells were treated with 25 μM EL for 24 and 48 h. The wound was observed for healing through migration and proliferation of cells by using phase invert microscope [Figure 1]a and b.
Figure 1b: Migration inhibition assay: Photo documentation at ×10
Figure 1a: Migration inhibition assay: Photo documentation at ×4


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Actin-based cell motility assay

MDA MB 231 cells were seeded on sterile coverslips in a 24-well plate in L-15 medium with 10% fetal bovine serum. When the cells reached to 100% confluency wound was prepared by scrapping off the cells using a sterile tip. Detached cells were washed off with phosphate buffered saline(PBS) buffer and the remaining cells were treated with 25 and 50 μM EL (Sigma) for 24 and 48 h in a fresh medium. The cells were observed for filopodia and lamellipodia structures by staining for polymerized actin by TRITC- Phalloidin, visualized at 24 and 48 h by using confocal imaging.

Reverse transcriptase- polymerase chain reaction


Drug-treated MDA MB 231 and MCF-7 breast cancer cells were harvested, and total RNA was isolated using TRIzol reagent (Invitrogen) and cDNA was prepared by using SuperScript TM first-strand synthesis system for RT-PCR (Invitrogen), according to the manufacturer's instructions. The primers for MMP2, MMP9, MMP11, MMP14 and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes were designed by using 'Gene -Runner' software [Table 1].
Table 1: List of primers

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The Reverse transcriptase- polymerase chain reaction (RT-PCR) was performed for five different genes by using eppendorf PCR thermal cycler. The PCR was carried out using 250 ng of DNA, 1 x PCR buffer with 1.5 mM of MgCl 2 , 12 ρmol of each primer (Ocimum biosolutions), 1U of Taq DNA polymerase (Bangalore genei) in a final volume of 25 μl. Steps of RT-PCR, were initial denaturation at 95 0 C for 1 min, then 35 cycles of denaturation at 94 0 C for 40 sec, annealing at variable temperatures for 40 sec, extension at 68 0 C for 50 sec followed by a 7-min final extension at 72 0 C. The annealing temperature for specific amplification reaction depended upon the TM of each set of primers of the specific gene. The PCR products were electrophoresed on 1% agarose gel and documented by a Gel-Documentation system after staining with ethidum bromide. Gene expression is quantitated in terms of the mean normalized gene expression, a ratio of the target gene to the reference gene, GAPDH. MMP2, MMP9, MMP11 and MMP14 expressions were standardized to GAPDH expression, assessed from the same cDNAs in separate PCR reactions and run in parallel on separate gels. Densitometry was performed by using Bio-Rad Quantity One Software.


 » Results Top


Migration inhibition assay

[Figure 1]a and b depict the effect of EL on the cell migration and cell proliferation on the MDA MB 231 cell lines. From the present study it can be seen that EL is capable of inhibiting the proliferation and migration of breast cancer cells even at 25 μM EL concentration, significantly.

Actin-based cell motility assay

The present study suggests that EL is capable of affecting the epithelial mesenchymal formation by polymerized actin thus affecting the actin-based cell motility of breast cancer cells in a dose-dependent and time-dependent manner, at both 25 and 50 μM EL concentrations. Confocal images of actin cytoskeleton of control, with 25 and 50 μM concentrations of EL are presented in [Figure 2]a (24 h) and 2b (48 h).
Figure 2a: Confocal imaging of actin cytoskeleton of control, 25 and 50 ìM concentrations of EL at 24 h
Figure 2b: Confocal imaging of actin cytoskeleton of control, 25 and 50 ìM concentrations of EL at 48 h


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Reverse transcriptase-polymerase chain reaction

RT-PCR products were analyzed by electrophoresis on 1% agarose gel [Figure 3]. Levels of gene expressions at 25 and 50 μM concentrations of EL , when compared with control, for MMP2 in MDA MB 231 [Figure 4], MMP2 in MCF-7 [Figure 5], MMP9 in MDA MB231 [Figure 6], MMP9 in MCF-7 [Figure 7], MMP-11 in MDA MB 231 [Figure 8], MMP11 in MCF-7 [Figure 9], and MMP14 in MDA MB 231 cell lines are depicted in [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9] and [Figure 10]. MMP-14 gene expression was studied in MDA MB 231 only [Figure 10].
Figure 3: Agarose gel electrophoresis on 1% agarose gel of RT-PCR products of GAPDH, MMP2, MMP9, MMP11 and MMP14 genes in MCF-7 and MDA MB 231 breast cancer cell lines treated with control, 25 μM and 50 μM concentrations of EL

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Figure 4: MMP2 expression in MDA MB 231

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Figure 5: MMP2 expression in MCF-7

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Figure 6: MMP9 expression in MDA MB 231

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Figure 7: MMP9 expression in MCF-7

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Figure 8: MMP11 expression in MDA MB 231

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Figure 9: MMP11 expression in MCF-7

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Figure 10: MMP14 expression in MDA MB 231

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Expression of MMP2 was down-regulated by about 19% and 23% at 25 μM and 50 μM drug treatment respectively, in the MDA MB 231 cell line [Figure 4]. Similarly, expression of MMP2 was reduced by about 20% and 21% at 25 μM and 50 μM drug treatment respectively, in the MCF-7 cell line [Figure 5]. Expression of MMP9 was reduced by about 11% and 18% at 25 μM and 50 μM drug treatment respectively, in MDA MB 231 cell line [Figure 6]. Similarly, in MCF-7 cell line, expression of MMP2 was reduced by 24% and 26% at 25 μM and 50 μM EL treatment respectively [Figure 7]. No significant change in the expression of MMP11 was observed at 25 μM EL concentrations in both MDA MB 231 and MCF-7 cell lines and only 10% reduction in expression at 50 μM EL treatment, in MCF-7 cell-line [Figure 8] and [Figure 9]. A significant change in the expression of MMP14 was observed with reduction in expression by 33% and 43% at 25 μM and 50 μM drug treatment respectively, in MDA MB 231 cell line [Figure 10]. Similar results were also observed in MCF-7 cell-line (data not shown). However, for statistical results further Real-Time PCR studies are required.


 » Discussion Top


Previous studies have shown that enterodiol (ED) and enterolactone (EL), metabolites of plant lignans exceptionally rich in flaxseed, and tamoxifen (TAM), alone or in combination, can influence the various steps of metastasis, that is, breast cancer cell adhesion, invasion and migration in two ER−human breast cancer cell lines, MDA-MB-435 and MDA-MB-231. [2] Further it has been shown that dietary flaxseed and/or its SDG can significantly inhibit spontaneous metastasis of human breast cancer in nude mice [10],[11] and experimental lung metastasis of murine melanoma. [12],[14] In addition, flaxseed and its lignan and oil components can reduce rat mammary tumor growth at a late stage of carcinogenesis [15] and the invasion to neighboring tissues. [16] Although taken together these findings suggest that certain flaxseed components, particularly lignans have the potential to inhibit metastasis by blocking the metastatic cascade, no suggestion to the mechanism has been made. Any agent which can inhibit the adhesion, invasion or migration processes, may therefore become a powerful tool in the prevention of metastasis. The present study demonstrates that the metabolic product of flax lignan, EL, can alter the metastasis process including cancer cell adhesion, invasion and migration. The study suggests cellular as well as molecular mechanisms by which flaxseed may inhibit experimental metastasis.

Adhesion and migration

According to a longstanding hypothesis, breast cancer dissemination should involve a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Moreover, it was thought for decades that metastasizing breast cancer cells (BCC) first disseminated to the lymph nodes (LN) before reaching peripheral blood (PB) and distant locations, including bone marrow (BM). However, it has now became clear that metastatic spreading occurs in about 50% of cases with apparently localized breast cancer, and that up to 30% of patients with LN-negative disease will develop distant metastases within five years. [13] Metastasis follows a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding ECM, which separates the tumor from adjoining tissue. [4] By degrading these proteins, cancer cells are able to break the ECM and escape and thus become metastatic. The different types of cell migration are regulated by different mechanisms. Reorganization of the actin cytoskeleton is the primary mechanism of cell motility and is essential for most types of cell migration. It is now widely accepted that the basic engine for gliding or crawling locomotion is the actin cytoskeleton and regulation of cancer cell motility through actin reorganization has been reviewed. [17],[18] Cell locomotion is undoubtedly complex, requiring coordinated activity of cytoskeletal, membrane, and adhesion systems. Actin filaments themselves are likely to be involved in multiple force-generating mechanisms like forward motility of the membrane at the front of the cell i.e. protrusion, forward movement of the nucleus and cell body i.e. traction and the last step in locomotion i.e. deadhesion and tail-retraction. Adhesion is required for protrusion to be converted into movement along the substrate. In both filopodia and lamellipodia structures, protrusion of the membrane is tightly coupled to polymerization of actin filaments at the leading edge. [6],[17] The present study suggests that EL is capable of affecting normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby actin-based cell adhesion and cell motility involving multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction.

Invasion

Tumor invasion plays a crucial role in metastasis and involves a number of important steps including adhesion of tumor cells to the BM; enzymatic digestion of the BM by proteolytic enzymes followed by migration through the ECM with the subsequent growth and proliferation of cells at a new site. [1],[18] MMPs are zinc-dependent endopeptidases and collectively they are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. Possible mechanisms by which MMPs contribute to cancer initiation or to tumor cell growth include promotion of angiogenesis, activation of stimulating growth factors or their receptors, and inactivation of inhibiting growth factors. [18] An additional step in the process of invasion involves degradation of the BM via proteolytic enzymes. MMPs display specific proteolytic activity against components of the ECM and their over-expression has been linked to invasiveness of breast cancer cells in vitro. [5] It is generally assumed that the primary mechanism by which MMPs promote cancer spread is by degradation of the ECM, which consists of two main components: basement membranes and interstitial connective tissue. Although Collagen IV is the main component of basement membranes, other proteins such as laminin, proteoglycans, entactin and osteonectin are also present in this structure. The Collagen IV component of basement membranes is thought to be degraded mostly by MMP2 and MMP9 and thus these MMPs may therefore play a critical role in the conversion of in situ breast cancers to invasive lesions. [19] Some studies also reported that ST3 (MMP11) enhances rather than initiates tumorigenesis by either activating ECM-bound signaling components or at least by synergistic effects with ECM-containing growth factors such as Insulin-like Growth Factor-I (IGF1). [20] MMP2 is secreted in an inactive pro-enzymatic form and, unlike other MMPs, its activity is modulated by tissue inhibitor of metalloproteases (TIMP)-2 and the membrane Type 1 MMP (MMP-14). [21] RT-PCR assay in the present study suggests that the EL is capable of decreasing the expression of MMP2, MMP9 and MMP14 genes significantly thereby possibly blocking the invasion of cancer cells through the BM.


 » Conclusion Top


In conclusion it can be stated that this is the first report suggesting the possible cellular and molecular mechanism involved in the anti-metastatic activity of EL mammalian lignan derived from dietary intake of flaxseed. Through cellular studies we show that EL possibly inhibits the migration and proliferation. The observation that EL down-regulates various metalloproteinases suggests that EL may also be inhibiting invasion. More in-depth molecular, cellular, animal and clinical studies are required to establish SDG from flaxseed and its active derivatives in mammalian system EL as an effective anti-metastatic drug.


 » Acknowledgment Top


The authors would like to acknowledge Dr. S.S. Kadam, Vice-chancellor, Bharati Vidyapeeth Deemed University, Pune, India, for providing necessary facilities to carry out the study. Financial support of ICAR NAIP projects on flaxseed to Bharati Vidyapeeth Deemed University [BVDU] is gratefully acknowledged.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
 
 
    Tables

  [Table 1]

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