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Targeting STAT Proteins for Cancer Therapy

© David Olle

Role of STAT proteins in normal cells

In order for cells to respond to their environment, external stimuli must be received and transmitted to the nucleus. This results in activation of genes that lead to specific biologic responses. STAT proteins are normal constituents of cells, the acronym standing for signal transduction and translation. The STAT proteins are a point of convergence for numerous signaling pathways that lead to cancer. Although there are seven STAT proteins, STAT-3 is the most commonly found in a large variety of cancers. The signal transduction phase begins with a growth factor or cytokine binding to their specific receptors on the cell membrane. This results in the activation of enzymes called tyrosine kinases, which in turn activate the STAT proteins. In the translation phase, the STAT protein migrates to the nucleus, where it binds to promoter elements on the DNA molecule, leading to expression of target genes.

How do cancer cells subvert STAT protein function?

Cancer cells can utilize a mechanism whereby tyrosine kinases not associated with specific receptors can activate STAT proteins directly. The resultant STAT proteins are in a state on constant activation, thereby bypassing the normal finely tuned control mechanisms. The effect of these "constitutive" STAT proteins is described in the following paragraphs. 4

STATs in tumor-cell proliferation and apoptosis

The p53 protein continuously monitors the state of the DNA molecule and its constituent genes. When defects or mutations are found, the levels of p53 rise, and bind to specific segments of the DNA, which activate or inactivate certain genes involved with cell growth. If the cell cannot repair the defects, p53 initiates apoptosis, or programmed cell death. STAT-3 has been shown to inhibit p53 gene expression, and therefore the functioning of this important tumor suppressor. Scientists have also shown that STAT-3 can promote the expression of genes that act to inhibit apoptosis.

Stats in tumor angiogenesis

In order for a tumor to continue to grow, it must also continue to develop new capillaries to provide nutrients and oxygen. The most potent angiogenesis-inducing signal is vascular endothelial growth factor. Studies have shown that STAT-3 is a direct transcriptional activator of the VEGF gene.

STAT-3 signaling in evasion of immune response to tumors

It has long been a dream of clinicians to use the natural immune response of the body in order to defeat cancer. However, this requires that the immune system recognize the cancer as a foreign invader. The immune system detects invading microorganisms due to the presence of foreign substances on their cell surfaces. There are generally little differences between normal and cancer cells, and most antigens are in the interior of cancer cells rather than on their surfaces. White blood cells known as macrophages continuously patrol the blood and lymphatic system looking for foreign substances. In cancer research, dendritic cells have received the most attention. When found, foreign cells are engulfed, digested, and antigen fragments presented on their cell surfaces. T-lymphocytes bind to the antigen complex, and are stimulated to secrete chemicals called cytokines. The cytokines further mobilize the immune system. It is an integrated process, with many feedback mechanisms. For further details, see my articles on Immunology (I and II).