Finding a New Angle to Colon Cancer: Lipid Droplets and Genistein

If you are lactose intolerant and rely on soy milk or simply love the taste of Silk®, there is good news for you. Recent studies have shown that genistein, a component of soy, has the ability to curb colon cancer progression and lower the risk of getting colon cancer.

According to the National Health and Nutrition Examination Survey, over one third of the U.S. population is obese [1]. As numerous studies have shown, obesity is linked to heart diseases and various kinds of cancer, including colorectal cancer, the second leading cause of death among cancer-related deaths. Approximately 50,830 patients die of colon cancer in a given year. How exactly is colon cancer and obesity linked? In recent years scientists have discovered previously unknown properties of the dynamic organelle known as lipid droplets (LD). Lipid droplets not only store intracellular fat but also play an important role in inflammation signaling and lipid metabolism. Tumor tissues from colon cancer patients have an increased number of lipid droplets compared to normal tissues. Although the mechanism underlying this correlation is still unclear, ongoing research at the Savkovic Lab at Tulane University has suggested that excess fat in the tissues lead to an accumulation of LDs, which in turn leads to the inactivation of the tumor suppressor FOXO3.

FOXO3 and the role it plays in cancer regulation

The FOXO genes control the presence of FOXO proteins, which are transcriptional factors that are deactivated upon phosphorylation. The “FOX” in the name comes from the location—the forkhead box—where these proteins bind DNA. In the context of this discussion, the protein we are primarily interested in is FOXO3, which suppresses tumor growth by increasing expression of the cell cycle inhibitor p27kip1. FOXO3 is also responsible for regulation of metabolic states and mitosis and induction of apoptosis. It is the downstream target of many pathways, including PI3K, casine kinase 1, DYRK1A, and IKK. All of these kinases phosphorylate FOXO3, which results in its translocation from the nucleus, where it is active, to the cytoplasm, where it is degraded [2].

Experiments have shown that FOXO3 deficient mice shows increased colon cancer proliferation and increased number of lipid droplets. The reason seems to be that aggregation of LDs in the cytosol forces FOXO3 out of the nucleus, which inactivates the repressor and leads to the progression of colon cancer cells [2,3].

Genistein saves the day

Genistein.svgOver the past decade, consumption of soy-related foods has received increased attention due to a number of studies that show the positive biological effects of ingesting genistein, a component of soybeans [4]. Genistein belongs to a class of phytochemicals called isoflavones, which structurally bears similarity to the female hormone 17B-estradiol. The initial research into genistein was prompted by its potential as a competing ligand for estrogen receptors in breast cancer tissues [5]. While it is still unclear whether genistein could do that, researchers at Kyoto Prefectural University of Medicine did find that genistein combined with I3C (another phytochemical) inhibits proliferation of colon cancer cells [6]. This is significant in that genistein is safely consumed by humans and the chemical’s ability to control proliferation of tumor cells may lead to exciting new alternatives to current cancer treatments. Interestingly, genistein seems to impede progression of cancer by preventing FOXO3 from being inactivated in colon cancer cells [3]. This prevention allows FOXO3 to continue it’s duty of indirectly inhibiting further cell development and division of cancer cells through p27kip1.

lipid droplets

This image shows genistein’s ability to decrease the number of lipid droplets by blocking stimuli that induces their formation. EGF (epidermal growth factor) is known to increase lipid droplets (as seen in the second row) [7]. The cells treated with genistein, however, show markedly decreased number of LDs. To complement immunostaining results, the cellular concentrations of PLIN2 (membrane protein on LDs) for different treatments are found through standard Western blots. Again, genistein blocks formation of LDs under signal from EGF—cancer cells often stimulate abnormal growth by releasing EGF to surrounding cells [7].

It is worth pointing out that LDs are primarily found in adipose tissues. The discussion of genistein and LDs is relevant in the study of colon cancer because the colon is wrapped in a layer of fat—the adipose tissue—that has lymph nodes and blood vessels which feed the colon tissue.

If genistein lowers LD density, then a soy-rich diet may significantly reduce chances of getting colon cancer in obese individuals. In addition, lowered LD density can decrease available energy for the high metabolic tumor cells [8]. Without as much energy, it is possible that tumor cells’ growth rate will slow. Most importantly, by lowering the number of LDs, genistein may be able to reactivate the tumor suppressor FOXO3, as discussed in previous paragraphs.

Genistein and other cancers

Can genistein’s effect on colon cancer cells be generalized to other cancers? The answer is still uncertain. In the case of breast cancers, researchers have shown that genistein alone did not decrease cancer-driven angiogenesis—the formation of new blood vessels that are key to progression. However, the paper did note that the combination of genistein and enterolactone (ENL), another promising anti-cancer drug, inhibited tumor growth [9]. Looking to the opposite sex, genistein has shown promising results for the treatment of prostate cancer both in vivo and in vitro; experimental data suggests that genistein accomplishes inhibition by regulating the oncogenic gene HOTAIR [10]. A recently published article on the results of a phase 2 biomarker trial testing genistein’s ability to forecast bladder cancer concluded that genistein “should be evaluated further, possibly in combination with other agents” [10]. The editor of the article noted that while many agents, like genistein, performed well in vitro they often fail once in the body [11]. Unlike homogenous cells cultured in a petri dish, the chemical response produced by the body to potential drug candidates such as genistein often proves to be more complex. Despite these difficulties, scientists continue the search for possible biomarkers or treatments for colon cancer and other cancers. Hopefully, the deliciousness of soymilk will turn out to do more for the body than pleasing our taste buds.

References

[1] Ogden, C.L., et al., Prevalence of obesity in the United States, 2009-2010. NCHS data brief, 2012: p. 1-8.

[2] Snoeks, L., et al., Tumor suppressor Foxo3a is involved in the regulation of lipopolysaccharide-induced interleukin-8 in intestinal HT-29 cells. Infection and immunity, 2008. 76: p. 4677-85.

[3] Savkovic, S.D., FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density. 2013.

[4] Le Marchand, L., Cancer preventive effects of flavonoids–a review. Biomedicine & pharmacotherapy = Biomédecine & pharmacothérapie, 2002. 56: p. 296-301.

[5] Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139 (10): 4252–63. doi:10.1210/en.139.10.4252. PMID 9751507.

[6] Nakamura, Y., et al., A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Molecular cancer, 2009. 8: p. 100.

[7] Qi, W., et al., Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC cancer, 2011. 11: p. 219.

[8] Walther, T.C. and R.V. Farese, Lipid droplets and cellular lipid metabolism. Annual review of biochemistry, 2012. 81: p. 687-714.

[9] Saarinen, N. M., Abrahamsson, A. and Dabrosin, C. (2010), Estrogen-induced angiogenic factors derived from stromal and cancer cells are differently regulated by enterolactone and genistein in human breast cancer in vivo. Int. J. Cancer, 127: 737–745. doi: 10.1002/ijc.25052

[10] Chiyomaru, Takeshi, et al. “Genistein Inhibits Prostate Cancer Cell Growth by Targeting miR-34a and Oncogenic HOTAIR.” Plos ONE 8, no. 8 (August 2013): 1-10. Academic Search Premier, EBSCOhost (accessed April 9, 2014).

[11] David P. Wood, Re: A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients, The Journal of Urology, 189, no. 4 (April 2013): 1287-1288, http://dx.doi.org/10.1016/j.juro.2013.01.006.

Image Credit:

[1] Retrieved September 3, 2014 from: Wikipedia. http://en.wikipedia.org/wiki/Genistein#mediaviewer/File:Genistein.svg

[2] Retrieved September 3, 2014 from: Qi, W., et al., Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC cancer, 2011. 11: p. 219.

 

Sharon Chen is a biology and art history double major at Northwestern University. She is the Director of Public Policy at the NU chapter. Follow The Triple Helix Online on Twitter and join us on Facebook

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