Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2‐overexpressing cancer cells

Abstract

Mollugin is a naphthohydroquine found in the roots of Rubia cordifolia, and has been reported to have a variety of biological activities, including anti-inflammatory and apoptotic effects. In the present study, we investigated the molecular mechanisms by which mollugin exerts anti-tumor effect in HER2-overexpressing cancer cells. Our results showed that mollugin exhibited potent inhibitory effects on cancer cell proliferation, especially in HER2-overexpressing SK-BR-3 human breast cancer cells and SK-OV-3 human ovarian cancer cells in a dose- and time-dependent manner without affecting immortalized normal mammary epithelial cell line MCF-10A. Furthermore, we found that a blockade of Akt/SREBP-1c signaling through mollugin treatment significantly reduced FAS expression and subsequently suppressed cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Mollugin treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. The combination of mollugin with a MEK1/2 inhibitor may be required in order to achieve optimal efficacy in HER2-overexpressing cancers. These data provide evidence that mollugin inhibits proliferation and induces apoptosis in HER2-overexpressing cancer cells by blocking expression of the FAS gene through modulation of a HER2/Akt/SREBP-1c signaling pathway. Our findings suggest that mollugin is a novel modulator of the HER2 pathway in HER2-overexpressing cancer cells with a potential role in the treatment and prevention of human breast and ovarian cancer with HER2 overexpression.

Involvement of Nrf2-Mediated Upregulation of Heme Oxygenase-1 in Mollugin-Induced Growth Inhibition and Apoptosis in Human Oral Cancer Cells

“…To explore the mechanism underlying mollugin-induced apoptosis in OSCCs, we examined NF- κ B activation. In agreement with previous findings that mollugin suppressed NF- κ B activation in HER2-overexpressing SK-BR-3 breast cancer cells [17], our results indicate that mollugin significantly inhibited NF- κ B activation by reducing the level of phospho-I κ B α , leading to blockage of the I κ B α pathway in NF- κ B activation in OSCCs. In addition, it was reported that mollugin significantly suppressed TNF- α -induced NF- κ B transcriptional activation in HT-29 human colonic epithelial cells [13].…”

“…In the present study, we found that mollugin (10–80  μ M) resulted in significant growth inhibition, with an average IC 50 value of 46.3  μ M in metastatic OSCCs (HN12) and 43.9  μ M in primary OSCCs (HN4) after 3 days. These antiproliferative properties of mollugin are consistent with previous reports in human acute leukemia Jurkat T cells [14] and HER2-overexpressing breast and ovarian cancer cell lines [17]. Moreover, we demonstrated that mollugin induced OSCC cell death by triggering apoptosis due to the presence of several apoptotic characteristics, including sub-G 1 phase accumulation, increase in annexin + /PI + cells, and DNA fragmentation.…”

“…With regard to antitumor activity, mollugin has been shown to exert cytotoxic effects on human colon cancer (Col2) cells (IC 50 = 12.3  μ M; [11]), human liver carcinoma (HepG2) cells (IC 50 value = 60.2  μ M; [10]), and basal HER2-expressing human breast cancer cells (IC 50 value = 58  μ M; [17]). In the present study, we found that mollugin (10–80  μ M) resulted in significant growth inhibition, with an average IC 50 value of 46.3  μ M in metastatic OSCCs (HN12) and 43.9  μ M in primary OSCCs (HN4) after 3 days.…”

“…A recent study demonstrated that mollugin induced apoptosis through endoplasmic reticulum stress-mediated activation of c-Jun N-terminal kinase (JNK) and the mitochondria-dependent caspase cascade, regulated by Bcl-xL in human Jurkat T cells [14]. Moreover, mollugin inhibited proliferation and induced apoptosis by suppressing fatty acid synthase in HER2-overexpressing human breast and ovarian cancer cells [17]. …”

Oxomollugin, a potential inhibitor of lipopolysaccharide-induced nitric oxide production including nuclear factor kappa B signals

“…Furthermore, mollugin inhibited the inflammatory response in LPS-stimulated RAW264.7 by blocking the JAK-STAT signaling pathway [10]. Mollugin was also reported to induce proliferation inhibition and apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells [11]; apoptosis and autophagy were also reported to be induced via the PI3 K/AKT/mTOR/p70S6 K and ERK signaling pathways [12]. Recently, Baek et al reported that mollugin suppresses RANKL-induced osteoclastogenesis and bone resorbing activity in vitro and prevents LPS-induced bone loss in vivo [13].…”