Volume 8 Issue 10 - May 22, 2009
Induction of autophagy by Concanavalin A and its application in anti-tumor therapy
Huan-Yao Lei*, Chih-Peng Chang

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University
hylei@mail.ncku.edu.tw

Autophagy, 2007, 3: 402-404.

 
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Liver cancer is the fifth most important cancer worldwide, and is the second cancer mortality in Taiwan. The major causes for hepatocellular carcinomas (HCC) are infection of hepatitis B, and C virus. The chronic active hepatitis is recognized as the major risk factor for HCC, and is accompanied by liver cell necrosis, inflammation, cytokine abnormal synthesis and fibrosis. The current treatment for hepatoma is not satisfactory, the major drawback being the common relapse after surgery or chemotherapy treatment. Concanavalin A (Con A), a lectin from Jack bean seeds that, once bound to the mannose moiety on the cell membrane glycoprotein, is internalized preferentially to the mitochondria. A BNIP3-mediated mitochondria autophagy is then induced, and causes the tumor cells to undergo autophagic cell death. In addition to the autophagy induction, Con A is known to be a T cell mitogen and has been shown to induce hepatitis in mice through the triggering of NK T cells and subsequent activation of CD4+ T cells. We have reported that Con A havs an anti-hepatoma therapeutic effect, inhibiting tumor nodule formation in the liver and prolonging the survival of the tumor-bearing mice. The anti-tumor effect is primarily mediated by activated CD8+ T cells, and will also establish a tumor antigen-specific immune memory that will inhibit the same tumor challenge later1. How Con A exert its anti-hepatoma effect? The liver, in its function as a filtering organ, can trap blood-born foreign substances, and its anatomic location and unique blood circulation makes it a good site to concentrate and bind Con A. Con A trapped in the liver would preferentially bind to hepatoma cells through its specific binding to the high content of mannose residue on tumor cell membranes. Con A accumulated in the liver nodules not only directly induces hepatoma cells to undergo autophagy, but also activates and recruits immune cells into the liver. This hepatic inflammation subsequently induces the adaptive immune response against the tumor and leads to liver tumor regression. Initially, the Con A effect is not tumor cell-specific, but as hepatic inflammation proceeds following Con A deposition, tumor antigens of the hepatoma cells will be processed and presented to the tumor antigen-specific CD4+ T and CD8+ T cells. Tumor-specific immunity is established thereafter.

Autophagy is emerging as new target for cancer therapy. Autophagy plays a protective role in maintaining energy homeostasis and protein and organelle quality control for normal cells. But for cancer cells, it becomes crucial because cancer cells demand high energy for their continuing uncontrolled proliferation. Autophagy functions are particularly important under metabolic stress condition. Any defects in the autophagy mechanism may lead to the accumulation of cellular damage and generation of reactive oxygen to cause genome instability, thus prompting tumor initiation and driving cell-autonomous tumor progression. It would further protect tumor cells from metabolic stress-induced damage and allows tumor cells to tolerate and recover from stress. It, therefore, can be viewed as a tumor suppression mechanism. If we can identify the molecules or pathways of autophagy that are required to suppress the tumorigenesis, and know which human tumor has deficient autophagy, then autophagy can emerge as a new target for cancer therapy. Although autophagy is to maintain cellular metabolism under starvation, remove damaged organelles under stress, and therefore improve the total survival capacity of cells. But, under certain circumstances, autophagy can lead to cell death. The level of autophagy might determine the final outcome, as moderate induction supports cell survival whereas massive and/or prolonged induction leads to cell death.

Chemotherapy remains the treatment modality of choice for most advanced cancer while immunotherapy is at the infant stage of cancer treatment. The two are regarded as either unrelated or sometimes antagonistic. However, recent studies have shown that the chemotherapy-induced tumor cell death process will engage with the anti-tumor immune response, and that the two modalities can be synergistically beneficial for cancer treatment. The best strategy of cancer therapy will be the association of both a direct cytotoxic drug effect and an indirect immune-mediated cytotoxic effect. The dual properties which Con A bears due to its specific mannose binding mean that it can perform both direct autophagic induction on target cells and also indirect immunomodulating activity on lymphocytes. In this sense, Con A is a novel type of endogenous cancer vaccine immunotherapy2. The combination effect of direct autophagic induction on target cells and indirect immunomodulating activity on lymphocytes via the mannose binding to tumor cells will induce an in situ inflammatory response and the subsequent anti-tumor response. This makes Con A as a potential candidate for a successful anti-hepatoma agent3, and opens a new exploration for natural lectins as anti-cancer compounds4.


References:
1.Chang CP, et al. Hepatology, 2007, 45: 286-296.
2.Lei HY, Chang CP. J Biomed Sci, 2009, 16:10.
3.Lei HY. ROC patent No. 281401.
4.Lei HY. ROC patent No. 292823.

Figure 1. The cover for paper published in Autophagy, July/August issue of 2007.
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