Dear,
can you kindly explain me whether an aberrant stimulation of mTOR signaling can lead genomic instability in order to promote cancer progression?
mTOR stimulation is a well-known pro-oncongenic pathway that provide energy to cancer cell in growht, but I would find a connection with genomic instability, I think that in anyway can be able to promote it.
Please, provide references...
Thank you in advance to everybody
Dear Marco,
It seems to me that mTOR is related to genomic instability in several ways. Firstly, mTOR functioning is inevitably involved in the PI3K/Akt pathway (see PMID 23744866). mTOR complexes 1 and 2 differentially regulate the pathway, while this pathway is the one contributing much to cell cycle progression thus the one contributing to genomic instability (see PMID 22869594). Secondly, mTOR counteracts autophagy (although these two pathways are not entirely mutually exclusive), while autophagy "inhibits early-stages oncogenesis by blocking genomic instability" (see PMIDs 24445999 and 24227992). Thirdly, mTOR itself has a somewhat direct influence on cell cycle progression (see PMIDs 14673156 and 19524688). Fourthly, "mTOR downstream effector S6 kinase, by phosphorylating a key enzyme of the pathway, stimulates nucleotide synthesis, thereby providing a link between the nucleotide pool required for increased RNA and DNA synthesis in growing cells" (see PMID 23687347).
Thus, at least autophagy counteraction is a direct effect of mTOR leading to genomic instability. Cell cycle progression overstimulation could also be contributory. Of course, nucleotide synthesis, being an mTOR effect, is not a direct factor of genomic instability, but rather an "accessory to the crime", unless - hypothetically - ROS-damaged nucleotides enter DNA synthesis on the high ROS background of at least some cancers (I have never seen a comprehensive paper on the damaged nucleotides metabolism, btw).
Many thanks, your reply was deep and clear. Thank Dr. Peter_Zolotukhin
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