Effect of Estrogen on Heteronemin-Induced Anti-proliferative Effect in Breast Cancer Cells With Different Estrogen Receptor Status

Abstract

Estrogen (E2) has multiple functions in breast cancers including stimulating cancer growth and interfering with chemotherapeutic efficacy. Heteronemin, a marine sesterterpenoid-type natural product, has cytotoxicity on cancer cells. Breast cancer cell lines, MCF-7 and MDA-MB-231, were used for investigating mechanisms involved in inhibitory effect of E2 on heteronemin-induced anti-proliferation in breast cancer cells with different estrogen receptor (ER) status. Cytotoxicity was detected by cell proliferation assay and flow cytometry, gene expressions were determined by qPCR, mechanisms were investigated by Western blot and Mitochondrial ROS assay. Heteronemin exhibited potent cytotoxic effects against both ER-positive and ER-negative breast cancer cells. E2 stimulated cell growth in ER-positive breast cancer cells. Heteronemin induced anti-proliferation via suppressing activation of ERK1/2 and STAT3. Heteronemin suppressed E2-induced proliferation in both breast cancer cells although some gene expressions and anti-proliferative effects were inhibited in the presence of E2 in MCF-7 and MDA-MB-231 cells with a higher concentration of heteronemin. Heteromenin decreased the Bcl-2/Bax ratio to inhibit proliferation in MDA-MB-231 but not in MCF-7 cells. Both heteronemin and E2 increased mitochondrial reactive oxygen species but combined treatment reversed superoxide dismutase (SOD)s accumulation in MCF-7 cells. Heteronemin caused G0/G1 phase arrest and reduced the percentage of cells in the S phase to suppress cancer cell growth. In conclusion, Heteronemin suppressed both ER-positive and ER-negative breast cancer cell proliferation. Interactions between E2 and heteronemin in signal transduction, gene expressions, and biological activities provide insights into the complex pathways by which anti-proliferation is induced by heteronemin in E2-replete environments.

Heteronemin Suppresses Lymphangiogenesis through ARF-1 and MMP-9/VE-Cadherin/Vimentin

“…Thus, it has been experimentally demonstrated that the marine environment is a very rich source for the discovery of anti-lymphangiogenic drugs. In addition, SP-1 has also been indicated to possess anti-cancer activity against various cancers [ 13 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Meanwhile, lymphangiogenesis enhances the metastatic outgrowth of cancer.…”

The power of heteronemin in cancers

“…The antiproliferative activities of 12-oxoheteronemin and heteronemin were evaluated additionally in six cancer cell lines and IC 50 values ranging from 0.66 to 1.35 µM were obtained [ 41 ]. Interestingly, heteronemin not only showed a strong potency in two estrogen receptor (ER)-positive breast cancer cells (MCF-7 and T-47D), but also exerted a notable antiproliferation in two ER-negative cell lines (MDA-MB-231 and Hs578T) [ 10 , 41 ]. Thus, heteronemin may both interfere with estrogenic steroid hormones and exhibit anticancer activity through other pathways without steroid receptors.…”

“…Heteronemin and its semisynthetic derivatives express important cytotoxic activity against a variety of tumor cells [ 7 – 9 ]. Heteronemin also disrupts various signal transduction pathways and has endocrine hormone interactions; these interactions include steroids [ 10 ] and thyroid hormones [ 11 , 12 ]. Additionally, the non-peptide hormones have been shown to interfere with the efficacy of anti-cancer drugs.…”

“…T 4 inhibits resveratrol-induced apoptosis by activating programmed death-ligand 1 (PD-L1) in ovarian cancer cells [ 16 ]. Estrogen blocks heteronemin-suppressed PD-L1 expression and anti-proliferation [ 10 ]. Recently, heteronemin has attracted the attention of pharmacologists and chemists mainly because of its potential anticancer properties.…”

“…Much more needs to be known about the molecular basis of heteronemin’s anticancer activity. Cellular uptake of the agent and actions of the drug on signal transduction pathways require further investigation, as do the mechanisms by which hormones and growth factors interfere with the heteronemin-induced anticancer activity [ 10 – 12 , 19 , 20 ]. The contributions of integrins in cancer progression have recently attracted attention in the literature [ 21 , 22 ].…”