Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Abstract

The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose-and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dosedependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects. (Cancer Sci 2011; 102: 1287-1292 B erberine is an isoquinoline alkaloid found in a number of important medicinal plant species such as Berberis aristata and Berberis aquifolium, and has antibacterial,(1) anti-hypertensive, (2) anti-inflammatory, (3) anti-diabetic (4) and anti-hyperlipidemic effects.(5) Recently, researchers have become interested in the anti-neoplastic activities of berberine and have demonstrated its anticancer effects against a variety of human cancer cells both in vitro and in vivo through suppression of tumor cell proliferation, induction of tumor cell apoptosis, and inhibition of both tumor invasion and metastasis.(6,7) These findings suggest that berberine is a promising candidate for clinical use in cancer chemotherapy.Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of death from cancer because of its very poor prognosis. More than 1 million cases of HCC occur in the world each year.(8) Hepatocellular carcinoma is highly resistant to conventional systemic therapies and the prognosis for patients with advanced HCC remains poor. Although a lot of progress has been made in terms of chemotherapy, which provides significant survival benefits for patients with HCC, it is associated with significant side-effects, highlighting the need for therapeutic strategies that target tumor cells without compromising normal tissue function.(9,10) Thus, the development of novel systemic agents from natural products with low toxicity and few side-effects is being actively pursued. (11)(12)(13) Previous studies confirm the anti-tumor effects of berberine on HCC. (14)(15)(16) Berberine acts by inhibiting proliferation and inducing apoptosis in HCC cells. It can also inhibit the migration of HCC cells by downregulating the Rho ⁄ ROCK signaling pathway.(17) However, the exact mechanisms underlying the anti-tumor effects of berberine are still unknown. CD147, a glycosylated immunoglobulin super family transmembrane protein, is highly expressed by HCC cells. Several in vitro studies suggest that CD147 promotes...

Effect of new berberine derivatives on colon cancer cells

“…Although few studies have described the ability of other BBR derivatives to induce autophagy, our data are in agreement with the results obtained with BBR in lung [16], liver [17], and hepatoma [18] cancer cell lines as well as in macrophages [19], adding a piece of information to the field of research aiming at investigating the proautophagic power of BBR [16][17][18][19]. The impact of autophagy on the response of cancer cells to BBR derivatives (and on their cytotoxicity) is still under investigation, in order to define whether this process could ensure cancer cell survival or act as a form of death, given that two opposite roles have been attributed to it [11,12,20,21].…”

Berberine sensitizes rapamycin-mediated human hepatoma cell death in vitro

“…Cell viability was determined using the MTT quantitative colorimetric assay. Our previous study showed that berberine inhibited HCC cell growth in a dose-and time-dependent manner at a concentration of 62.5 µM (12); thus in the present study, berberine was used at a concentration of 62.5 µM in combination with rapamycin. In brief, SMMC7721 and HepG2 cells were plated at a density of 5x10 3 cells/well on 96-well culture plates in RPMI-1640 medium supplemented with 10% FBS.…”

CD147 regulates apoptosis in mouse spermatocytes but not spermatogonia

“…While the role of CD147 in migration and metastasis of cancer cells has been well established (Kanekura and Chen, 2010;Weidle et al, 2010;Wu et al, 2011), recent studies have revealed that knockdown of CD147 by small-interfering RNA or blocking functional CD147 with a specific antibody inhibit the proliferation and tumorigenecity of multiple cancer cells (Chen et al, 2006;Abraham et al, 2008;Wang et al, 2010;Zhu et al, 2011) or induce massive cell death in colon (Baba et al, 2008) and liver cancer cells (Hou et al, 2011). These results suggest that CD147 has dual roles in regulating both migration and cell survival in cancer cells.…”