Abnormal protein phosphorylation- an indicator of cancer
Proteins are is an important components of the cells that make up the human body. They are It is a complex molecules that contains carbon atoms attached to other atoms namely hydrogen, nitrogen and oxygen to form an essential biomolecules.
The function of various proteins is facilitated by modifications of that specific proteins through the mRNA. These are known as post-translational modifications, the most common of which is phosphorylation.
The addition of a phosphoryl group (PO3-) to the protein molecule is known as protein phosphorylation. This conversion utilizes enzymes such as kinases and phosphotransferases.
Protein phosphorylation is vital for cellular processes to trigger signalling for specific tasks involving cell growth, proliferation, differentiation, metabolism, survival, movement,otility, aging and gene transcription. Abnormal protein phosphorylation to these signals results in disease, especially cancer tumour growth by promoting cancer cell formationproliferation, inhibiting cancer cell death, and inducing cancer cells to spread (metastasis).
Thus, cancers occur when changes (mutations), defects/malfunction in the regulatory mechanisms cause abnormal signalling pathways of protein phosphorylation.
Tyrosine kinases are important mediators of this signalling process. Initial animal studies established the key role of tyrosine kinase in abnormal cell growth leading to cancer tumor formation (oncogenesis). Soon, similar findings were reported in different types of cancers among humans.
Once the drivers/signals of cancer growth were identified the scientists started to look for medicines that could target the specific cancer cells with such mutations. As a result, researchers could produce began to identify drugs that target tyrosine kinases to treat cancers. Such medicines are called Tyrosine Kinase Inhibitors or TKIs.
Many such tyrosine kinase inhibitors are available today to treat various cancers: some of these are include imatinib used in the treatment of chronic myeloid leukemia (CML), gefitinib/erlotinib and crizotinib for lung cancers, vemurafenib for melanoma, sorafenib for kidney and liver cancer and , trastuzumab for breast cancer etc. Though the success rates with these drugs is heartening, there is always a possibility of resistance to these therapies. Each of the drugs used must act on the specific cancer tyrosine kinase and be able to alter the structure of the signalling network to cause t cancerumor cell death.
For this, patient selection is key: a release of tumor molecules circulating in the bloodstream can be tracked through a blood/saliva/ tissue sample test (RT-PCR) and used as biomarkers of cancer.
In CML, for example, imatinib therapy is chosen if the blood report shows BCR-Abl-positive result since these patients have BCR and ABL (Philadelphia chromosome genes) fused together by means of an activated protein tyrosine kinase. It may be important to consider that not all tumors respond to kinase inhibitors and in addition, often patients with the same cancer respond differently to the same therapy.
Nitric oxide, another key player in signalling pathway to protein phosphorylation has also been observed in different types of cancers including breast, lung, prostate, colon, gastric, pancreatic, and ovarian cancers, as well as in neuroblastoma. Recently, it has been established that a proper concentration of nitic oxide within the cells is vital to inhibit oncogenesis and metastasis. Drugs to target this pathway in abnormal protein phosphorylation are being explored to further reduce cancer tumor burden in patients.