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Point 6 for Cancer Success

Point 6 for Cancer Success

10 Points for Cancer – Point Six: Suppressing Ras/Raf Oncogene Expression

The family of proteins known as “Ras” and “Raf” play a central role in the regulation of cell growth – and in cancer, they suppress, or slow growth. They fulfill this fundamental role by integrating the regulatory signals that govern the cell cycle and proliferation, something grossly out of balance in a growing tumor. This means that Ras oncogenes help ‘turn-on’ normal cell death.

Defects in the Ras-Raf pathway can result in uncontrolled cancerous growth. Mutant Ras genes were among the first oncogenes identified for their ability to transform cells into a cancerous phenotype (i.e. a cell observably altered because of distorted gene expression). Mutations in one of three genes (H, N, or K-Ras) encoding Ras proteins are associated with upregulated (increasing) cell proliferation (growth) and are found in an estimated 30-40% of all human cancers. The highest incidences of Ras mutations are found in cancers of the pancreas (80%), colon (50%), thyroid (50%), lung (40%), liver (30%), melanoma (30%), and myeloid leukemia (30%) (Duursma 2003; Minamoto 2000; Vachtenheim 1997; Bartram 1988; Bos 1989; Minamoto 2000; Hsieh JS 2005; Däbritz J 2009).

The differences between oncogenes and normal genes can be slight. The mutant protein that an oncogene ultimately creates may differ from the healthy version by only a single amino acid, but this subtle variation can radically alter the protein’s functionality. Remember, proteins are just a long chain of amino acids; one seemingly small change changes everything. The Ras-Raf pathway is used by human cells to transmit signals from the cell surface (the membrane) to the cell nucleus. Such signals direct cells to divide, differentiate, or even undergo programmed cell death (apoptosis), therefore the SIGNALS ARE IMPORTANT.

inhibits

Signals

A Ras gene usually behaves as a relay switch within the signal pathway that instructs the cell to divide. In response to stimuli transmitted to the cell from outside, cell-signaling pathways are turned “on”. In the absence of stimulus, the Ras protein remains in the “off” position. A mutated Ras protein gene behaves like a switch stuck on the “on” position, continuously misinforming the cell, instructing it to divide when the cycle should be turned off (Gibbs et al. 1996; Oliff et al. 1996). So, the question is: How do you turn this switch “off”?

When we understand the physiology behind your body’s making Ras genes, we can begin to understand how to manipulate them. The events resulting in maturation of Ras genes take place in three steps, the most critical being the first—referred to as the ‘farnesylation step’. A specific enzyme, farnesyl-protein transferase (FPTase), speeds up the reaction. One strategy for blocking Ras protein activity has been to inhibit FPTase. Inhibitors of this enzyme block the maturation of Ras protein and reverse the cancerous transformation induced by mutant Ras genes (Oliff et al. 1996).

A number of natural substances impact the activity of Ras oncogenes. For example, limonene is a substance found in the essential oils of citrus products. Limonene has been shown to act as a farnesyl transferase inhibitor (i.e., it turns off the switch). Administering high doses of limonene to cancer-bearing animals blocks the farnesylation of Ras, thus inhibiting cell replication (Bland 2001; Asamoto et al. 2002). Curcumin also inhibited the farnesylation of RAS, and caused cell death in breast cancer cells expressing RAS mutations (Kim et al. 2001; Chen et al. 1997).

Point 6 for Cancer SuccessJapanese researchers examined the effects of vitamin E on the presence of K-Ras mutations in mice with lung cancer. Prior to treatment with vitamin E, K-Ras mutations were present in 64% of the mice. After treatment with vitamin E, only 18% of the mice expressed K-Ras mutations (Yano et al. 1997). Vitamin E decreased levels of H-Ras proteins in cultured melanoma cells (Prasad et al. 1990). A study conducted at Mercy Hospital of Pittsburgh also showed that diallyl disulfide, a naturally occurring organosulfide from garlic, inhibits p21 H-Ras oncogenes, displaying a significant restraining effect on tumor growth (Singh et al. 2000).

Researchers at Rutgers University investigated the ability of different green and black tea polyphenols to inhibit H-Ras oncogenes. The Rutgers team found that all the major polyphenols contained in green and black tea except epicatechin showed strong inhibition of cell growth (Chung et al. 1999). Investigators at Texas A&M University also found that fish oil decreased colonic Ras membrane localization and reduced tumor formation in rats. In view of the central role of oncogenic Ras in the development of colon cancer, the finding that essential fatty acids modulate Ras activation could explain why good omegas protect against colon cancer (Collett et al. 2001).

How to implement point six

Consider the following to inhibit the activity of Ras oncogenes:

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