Author and Reporter: Ritu Saxena, Ph.D.
Word Cloud By Danielle Smolyar
Mitochondria is an important cell organelle that is associated with several key cellular functions as energy production, anabolism, calcium homeostasis and cell programmed death, and any abnormalities occurring in mitochondria would lead to alteration of normal cellular function.
Role of mitochondria in cancer has long been implicated. Post published on September 1, 2012 (http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/) presents a brief overview of the mechanisms by which mitochondrial defects could be associated with cancer. Different studies on various types of Cancers have tried to determine the mtDNA mutations and the mechanisms involved. An important aspect of cancerous progression is the cancer cell migration and it has been observed that mitochondrial dysfunction is involved in cancer cell migration. However, the molecular mechanism still needs to be deciphered.
A group from Taiwan recently published their findings in the Biochimica et Biophysica Acta journal stating that enhanced β5-integrin expression was involved in promoting cell migration in human gastric cancer cell line as a result of mitochondrial dysfunction.
The authors used human gastric cancer cell line, SC-M1 cells for their studies. The methodology followed was to first create mitochondrial dysfunction in the SC-M1 cells by the use of oxidative phosphorylation inhibitors: oligomycin (Complex V inhibitor) and antimycin A (Complex III inhibitor) thereby inhibiting mitochondrial function. The results indicated that impaired oxidative phosphorylation caused an increase in the intracellular Reactive Oxygen Species (ROS) that lead to an increased cell migration in SC-M1 cells.
Different types of integrin molecules have been implicated in cell migration. Hung et al extracted RNA and protein from SC-M1 cells in order to study the different types of integrins, and observed that the levels of β5-integrin were significantly upregulated in SC-M1 cells. Simultaneously, the surface expression of the dimer- β5-integrin and αv-integrin, was studied in cancer cells with using FACS. The analysis revealed a higher surface expression of the dimer corresponding to the higher levels of the protein and RNA results of β5-integrin expression in SC-M1 cells with mitochondrial dysfunction. Infact, a subpopulation of SC-M1 cells that showed higher migration capability (SC-M1-3rd) was observed to harbor a higher lever of β5-integrin expression, correlating β5-integrin expression with cell migration ability. The experiments supported the role of β5-integrin in cell migration in gastric cancer cells.
Finally, authors confirmed the in vitro results in the human gastric cancer samples. Immunohistochemical analysis revealed that β5-integrin was stained positive in around 73% of the cancer samples. Additionally, the higher expression levels of β5-integrin could be correlated with the invasive ability and more aggressive behavior of gastric cancer cells.
Authors stated “our study pinpoints another aspect that links the induction of intracellular ROS level in mitochondrial dysfunction gastric cancer cells with the activation of αvβ5-integrin. Taken together, the induction of β5-integrin is important to gastric cancer metastasis, especially in cancer cells that exhibit mitochondrial dysfunction.”
Thus, blockage of αvβ5-integrin function by antibodies might be tested as a potential therapy for preventing or delaying gastric cancer metastasis, especially in gastric cancers harboring mitochondrial dysfunction.
Sources:
Research article: http://www.ncbi.nlm.nih.gov/pubmed?term=22561002
Related posts: http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/
http://pharmaceuticalintelligence.com/2012/08/14/detecting-potential-toxicity-in-mitochondria/
GREAT WORK, Ritu.
How about the category: Human Immune System?
Yet another association of vitronectin-binding integrin (alphaV-containing) upregulation in metastatic cancer. Please also see and incorporated references: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0036753
Gastric cancer is rare in the Western hemisphere, but not so rare in Japan. The most aggressively invasive is LINITIS PLASTICA, which goes through the wall and plasters the epigastric peritoneum. This type of invasion would be similar to ovarian caking of the peritoneum. I have not thought about it since my mothers death.
The incidence is not as rare as 40 years ago. It was surmised that there is an association with grill type cooking. There are a few points to think about:
1. Mitochondrial association should tend to be maternal transmission, which I’m not sure is the case. More likely, I would think that it is EPIgenetic.
2. There should be a relationship to prolonged high stress, which would have an effect in disrupting the immune system and increasing ROS. This is beyond what we know about it.
3. This finding could enable pathology diagnosis with histological staining. But I don’t see how early diagnosis will be possible in this case.
Larry, thanks for the comment. You have raised some very important points about Gastric Cancer. Litinits plastica, as you suggested is a more invasive form of gastric cancer so according to the report, there might be a correlation between the invasive nature of the cells and their integrin levels. Therefore, it it might be interesting to look at the beta5-integrin levels in the tissue samples through immunostaining.
There could definitely be a relationship to prolonged stress leading to ROS production, even in the case of mitochondria. Somatic mutations caused due to stress in any form would, I suppose, lead to disruption of mitochondrial function and in case it leads to ROS production, there could be several pathways activation consequently resulting in cancerous cells.
Also, I doublt that immunohistochemcial staining of beta5 integrin could be used as a pathological diagnosis method of gastric cancer. It might be a good indicator of later stages of cancer progression including metastasis. However, I could be wrong as integrins have been all over the place.
Ritu
Thank you for your comment.
Please reply to Meg’s comment above, please.
I agree with Larry, it seems epigenetics.
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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.
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