Human Müllerian inhibiting substance: Enhanced purification imparts biochemical stability and restores antiproliferative effects

Ragin, Richard C.; Donahoe, Patricia K.; Kenneally, Mary; Ahmad, Mir F.; MacLaughlin, David T.

doi:10.1016/1046-5928(92)90020-w

Cited by 61 publications

(54 citation statements)

References 37 publications

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“…31, and it was purified from the serum-free media by a combination of ammonium sulfate precipitation or lectin affinity followed by FPLC anion-exchange chromatography, described by Colony Assays. Cells were stably transfected at 80% confluence in 10-cm plates with 0.6 g of a hygromycin-resistance plasmid and 5.4 g of expression constructs consisting of empty vector, full-length MIS, leaderless (nonsecreted) MIS (34), p107, p130, E2F1, and a small interfering RNA vector for E2F1 by using FuGENE 6 transfection reagent (Roche Diagnostics, Indianapolis) and its accompanying protocol.…”

Section: Methodsmentioning

confidence: 99%

Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance

Renaud

MacLaughlin

Oliva

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Mullerian Inhibiting Substance (MIS), a 140-kDa homodimer glycoprotein member of the TGF-β superfamily of biological-response modifiers, causes regression of the Mullerian ducts in developing male embryos. MIS also can induce growth arrest and apoptosis in ovarian and cervical cancer cell lines. The embryonic progenitor of the ovarian and cervical epithelium is the coelomic epithelium, the same tissue that regresses under the direction of MIS in the male. The endometrium and uterus also arise from the coelomic epithelium and the Mullerian ducts. Here, we show that both normal human endometrium and endometrial cancers express the receptor for MIS and that MIS can inhibit the proliferation of a number of human endometrial cancer cell lines that express the MIS type II receptor. In the representative endometrial cancer cell line AN3CA, MIS affects the expression of key cell-cycle regulatory proteins. This work broadens the scope of tumors that MIS can potentially control and, by elucidating the MIS signaling pathway, identifies other potential avenues for intervention

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Section: Methodsmentioning

confidence: 99%

Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance

Renaud

MacLaughlin

Oliva

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…25 The cells were treated with AMH at different concentrations in 10% female fetal calf serum (FFCS; ie, no AMH in the control medium) for 1-10 days, followed by MTT, bromodeoxyuridine (BrdU), caspase activation, and DAPI staining assays (see below), or protein extraction. The used AMH concentrations (0-25 mg/ml or 0-179 nm) were similar to those used in epithelial ovarian carcinoma cell studies and in AMH bioactivity assays utilizing this particular AMH stock 20,22,[46][47][48][49] that is only partially cleaved (ie, activated) compared with fully cleaved AMH stocks that were recently established. 50,51 The K d of AMH binding to AMHRII in ovarian carcinoma cell lines (OVCAR5 and OVCAR8) was calculated to be 10.2 nM and 12 nM, respectively, 20,22 and we estimated the K d to be similar in this study.…”

Section: Cell Cultures and Treatmentsmentioning

confidence: 99%

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

Anttonen

Färkkilä

Tauriala

et al. 2011

Laboratory Investigation

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Ovarian granulosa cell tumors (GCTs) are sex cord stromal tumors that constitute 3-5% of all ovarian cancers. GCTs usually present with an indolent course but there is a high risk of recurrence, which associates with increased mortality, and targeted treatments would be desirable. Anti-Mü llerian hormone (AMH), a key factor regulating sexual differentiation of the reproductive organs, has been implicated as a growth inhibitor in ovarian cancer. GCTs and normal granulosa cells produce AMH, but its expression in large GCTs is usually downregulated. Further, as the lack of specific AMHsignaling pathway components leads to GCT development in mice, we hypothesized that AMH inhibits growth of GCTs. Utilizing a large panel of human GCT tissue samples, we found that AMH type I receptors (ALK2, ALK3 and ALK6) and type II receptor (AMHRII), as well as their downstream effectors Smad1/5, are expressed and active in GCTs. AMHRII expression was detected in the vast majority (96%) of GCTs and correlated with AMH mRNA and protein expression. AMH mRNA level was low in large GCTs, confirming previous findings on low-AMH protein expression in large human as well as mouse GCTs. To study the functional role of AMH in this peculiar ovarian cancer, we utilized a human GCT cell line (KGN) and 10 primary GCT cell cultures. We found that the AMH-Smad1/5-signaling pathway was active in these cells, and that exogenous AMH further activated Smad1/5 in KGN cells. Furthermore, AMH treatment reduced the number of KGN cells and primary GCT cells, with increasing amounts of AMH leading to augmented activation of caspase-3 and subsequent apoptosis. All in all, these data support the premise that AMH is a growth inhibitor of GCTs.

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“…Cells were treated with doxorubicin (NovaPlus), cisplatin (NovaPlus), or MIS. MIS was purified as previously described (52), and its bioactivity was assessed in embryonic Mullerian duct regression assays (53).…”

Section: Methodsmentioning

confidence: 99%

Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

Meirelles¹,

Benedict²,

Dombkowski³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad−) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad− cells. Similarly, proliferation of the 3+Ecad− cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3−Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad− subpopulation through the induction of cyclindependent kinase inhibitors. 3+Ecad− cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics. chemotherapy with cisplatin | pluripotency factors

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Human Müllerian inhibiting substance: Enhanced purification imparts biochemical stability and restores antiproliferative effects

Cited by 61 publications

References 37 publications

Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance

Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

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