In vitro and in vivo anticarcinogenic effects of RNase MC2, a ribonuclease isolated from dietary bitter gourd, toward human liver cancer cells

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 04/2012; 44(8):1351-60. DOI: 10.1016/j.biocel.2012.04.013
Source: PubMed


Hepatocellular carcinoma (HCC) constitutes a predominant part of primary liver cancer which ranks as the fifth most common cancer as well as the third most common cause of cancer mortality. In view of the poor prognosis of unresectable liver cancers, it is of pivotal importance to develop novel chemotherapeutical regimens. RNase MC2 is a 14-kDa ribonuclease isolated from dietary bitter gourd (Momordica charantia) that manifested antitumor potential against breast cancers. In this study, we investigated the potential application of RNase MC2 on Hep G2 cells. We showed that RNase MC2 inhibited cell proliferation and induced cell apoptosis in both in vitro and in vivo studies. RNase MC2 treatment caused cell cycle arrest predominantly at the S-phase and apoptosis, which is associated with the activation of both caspase-8 and caspase-9 regulated caspase pathways. Our further investigation disclosed that RNase MC2 down-regulated the anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bak. Moreover, the phosphorylation of ERK and JNK was involved in the apoptosis process. Importantly, RNase MC2 significantly suppressed the growth of Hep G2 xenograft-bearing nude mice by inducing apoptosis. This notion is supported by data indicating an increased number of caspase-3- and PARP-positive cells, and TUNEL-positive cells in RNase MC2-treated tumor tissues. In summary, we have revealed the antitumor potential of RNase MC2 toward Hep G2 cells. Considering that bitter gourd is a common dietary component in many countries, this study may help to prompt the clinical application of RNase MC2.

Download full-text


Available from: Chris Zhiyi Zhang, Jul 10, 2014
  • Source
    • "Because the antitumor effects are attributed to a new mechanism, cytotoxic RNases are attracting attention as potent anticancer reagents or alternatives to conventional DNA-damaging anticancer drugs. Investigations to find novel medicinal RNases, regardless of the species, have been actively performed and have identified several new RNases such as RNase from Lyophyllum shimeji [88], RNase MC2 from Momordica charantia [89], and Amphinase from R. pipiens [90] that exhibit antitumor effects. On the contrary, efforts to construct the effective variants or RNases-fusion molecules to make RNase more selective or stronger are now taking advantage of the latest genetic and protein engineering techniques. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sialic acid-binding lectin (SBL), isolated from oocytes of Rana catesbeiana, is leczyme and has both lectin and ribonuclease (RNase) activities. A remarkable antitumor effect of SBL has also been reported. SBL agglutinates various kinds of tumor cells but not normal cells. SBL agglutination activity is not affected by mono- or oligosaccharides. However, SBL-induced agglutination and antitumor effects are inhibited by sialomucin but not asialomucin. In addition, SBL has very little effect on sialidase-treated cells. SBL causes cancer-selective induction of apoptosis by multiple signaling pathways, which target RNA. Synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL) and interferon- γ (IFN- γ ), have been reported. Thus, SBL may be a novel candidate molecule for anticancer drug development. Sialoglycoconjugates on the tumor cell surface may be associated with lectin activity and antitumor effects of SBL. We review the properties of SBL, particularly its lectin, RNase, and antitumor activities, and comprehensively examine the potential application of SBL for clinical purposes.
    Full-text · Article · Apr 2014 · BioMed Research International
  • Source
    • "It was reported that activation of JNK is important for cytotoxicity of onconase using jnk1−/− jnk2−/− mouse embryo fibroblast (MEF) cells (53). Fang et al reported that RNase MC2 induces phosphorylation of p38, JNK and ERK in MCF-7 cells (3) and this RNase-mediated apoptotic signaling is contributed by dual phosphorylation of ERK and JNK in Hep G2 cells (54). Although it has been implicated largely that activation of p38 and JNK are proapoptotic (50,55) and that phosphorylation of ERK is linked with both antitumor activity (56) and tumor progression (57), some complicated results have been reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sialic acid binding lectin (SBL) isolated from Rana catesbeiana oocytes is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity. However, the mechanism of antitumor effects of SBL is unclear to date and the validity for human leukemia cells has not been fully studied. We report here that SBL shows cytotoxicity for some human leukemia cell lines including multidrug-resistant (MDR) cells. The precise mechanisms of SBL-induced apoptotic signals were analyzed by combinational usage of specific caspase inhibitors and the mitochondrial membrane depolarization detector JC-1. It was demonstrated that SBL causes mitochondrial perturbation and the apoptotic signal is amplified by caspases and cell death is executed in a caspase-dependent manner. The efficacy of this combinational usage was shown for the first time, to distinguish the apoptotic pathway in detail. SBL selectively kills tumor cells, is able to exhibit cytotoxicity regardless of P-glycoprotein expression and has potential as an alternative to conventional DNA-damaging anticancer drugs.
    Full-text · Article · Sep 2013 · International Journal of Oncology
  • Source
    • "The Bax/Bcl-2 ratio can be recognized as a key factor for apoptotic process by regulating cytochrome c from mitochondria to cytosol [51, 52]. Extract of M. charantia was reported to inhibit growth of several cancer cells by augmenting Bax/Bcl-2, Bad/Bcl-2, or Bak/Bcl-2 [36, 53]. Our results showed that Bcl-2 was significantly decreased and Bax was increased in MCME-treated cancer cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plants are an invaluable source of potential new anti-cancer drugs. Momordica charantia is one of these plants with both edible and medical value and reported to exhibit anticancer activity. To explore the potential effectiveness of Momordica charantia , methanol extract of Momordica charantia (MCME) was used to evaluate the cytotoxic activity on four human cancer cell lines, Hone-1 nasopharyngeal carcinoma cells, AGS gastric adenocarcinoma cells, HCT-116 colorectal carcinoma cells, and CL1-0 lung adenocarcinoma cells, in this study. MCME showed cytotoxic activity towards all cancer cells tested, with the approximate IC 50 ranging from 0.25 to 0.35 mg/mL at 24 h. MCME induced cell death was found to be time-dependent in these cells. Apoptosis was demonstrated by DAPI staining and DNA fragmentation analysis using agarose gel electrophoresis. MCME activated caspase-3 and enhanced the cleavage of downstream DFF45 and PARP, subsequently leading to DNA fragmentation and nuclear condensation. The apoptogenic protein, Bax, was increased, whereas Bcl-2 was decreased after treating for 24 h in all cancer cells, indicating the involvement of mitochondrial pathway in MCME-induced cell death. These findings indicate that MCME has cytotoxic effects on human cancer cells and exhibits promising anti-cancer activity by triggering apoptosis through the regulation of caspases and mitochondria.
    Full-text · Article · Oct 2012 · Evidence-based Complementary and Alternative Medicine
Show more