Author and Reporter: Anamika Sarkar, Ph.D.
Targeted therapies are proven approaches in Cancer and other complicated diseases. Degrees of activation of measured EGFR and ERB2/HER2 in cancer cells are thought of one of the ways to identify the scale of aggressiveness of cancer in tissues. There are drugs, mostly for breast cancer, which targets inhibition of these receptors. Lapatinib (Tykerb, GSK – see Source for other targeted drugs) is the first drug which inhibits both EGFR and ERB2/HER2 gave hope to cancer patients, especially advanced ERB2-postive or metastatic breast cancer patients. Despite of proven high efficacy, Lapatinib didn’t show promising results in clinical responses due to acquired resistance.
Komurov et. al. (Mol. Systems.Biol., 2012) used network analysis along with experimental findings on cultured human breast cancer cell lines (SKBR3) and showed that a large part of acquired resistance to Lapatinib is due to increased levels of activated states of glucose deprivation signaling network. The authors cultured ERB2-positive SKBR3 cells with increasing doses of Lapatinib, to make the control cell lines for analyzing their experimental results in comparison with (SKBR3- R),SKBR3-Resistant cells. Their Western Blot analysis showed that Lapatinib was successful to inhibit down signaling pathways to ERB2 and EGFR in both control and resistant cells however fails to induce apoptotic pathways in resistant cells when compared with the controlled cells.
To identify other factors which can influence the differential effects of Lapatinib on controlled and resistant cell lines, Komurov et. al. used a data biased random walk network analysis method called Netwalk (Komurov et. al. PLOS Comp Biol., 2010). Their method is data driven and based on comparative network analysis of gene expressions at different conditions rather than network analysis at one gene level. Their network analysis identified presence of high levels of genes which act as compensatory mechanisms for glucose deprivation (as shown in Figure 2 of the paper Komurov et. al. (2012) Figure 2). They showed validation of their network analysis findings using Western Blot analysis (as shown in Figure 3 of the paper Komurov et.al. (2012) Figure 3).
The authors’ results not only show a nice elegant way of finding new information using network analysis and experimental techniques together, but also points out an important concept which can be future of cancer therapy. Their results show that along with targeting mutated Oncogenes eg., EGFR and ERB2/HER2 as in case of Lapatinib, additional way of controlling the pathway of deprivation of glucose, can achieve better clinical responses for cancer patients with aggressive levels of cancer. Targeting glucose or pathways of glucose can be tricky, because of its ubiquitous links to many physiological functions, including metabolism. However, the levels at which these pathways need to be targeted to achieve certain positive responses at in-vitro, supported by systems biology methods, and then in-vivo studies can be informative. Moreover, targeting many parts in the network in smaller amounts, along with targeted cancer drugs, may produce interesting results.
Sources:
Komurov et.al. (2012) : http://www.ncbi.nlm.nih.gov/pubmed/22864381
A News and Views on Lapatinib (2005) : http://www.emilywaltz.com/Herceptin.pdf
Komurov et.al. (2010) – Article published on methods of Netwalk : http://www.ncbi.nlm.nih.gov/pubmed/20808879
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.