mTOR and Contact Inhibition

Contact inhibition is a mechanism that suppresses cell division, halting the cell cycle in a densely packed cluster of cells. Much more efficient contact inhibition is presently a leading candidate for the reason why naked mole-rats do not suffer cancer: cancer creates dense masses of cells, and thus is halted at the outset in this species. There is considerable interest in the research community in finding ways to exploit this sort of mechanism, bringing it to humans as a therapy of some sort. Hence investigations are presently underway on a range of related mechanisms in cellular biology.

Here a researcher focused on the role of mTOR considers contact inhibition in that context, which spans cancer, cellular senescence, and numerous other aspects of aging. Of particular interest are the mechanisms determining the difference between reversible arrest of cell division, called quiescence, and irreversible arrest as occurs in cellular senescence:

Numerous studies have been aimed to pinpoint the difference between quiescence and senescence based on either the point of cell cycle arrest, the nature of stresses or peculiarities of Cyclin Dependent Kinase-inhibitor (CDKi)-induced arrest (p21 versus p16). Yet, despite all efforts, the distinction remained elusive. In fact, the difference between quiescence and senescence lies outside the cell cycle. A senescent program consists of two steps: cell cycle arrest and mitogen-activated and growth-promoting signaling pathways. Rapamycin suppresses geroconversion, maintaining quiescence instead. Furthermore, any condition that directly or indirectly inhibits mTOR in turn suppresses geroconversion.

The two-step model is applicable to contact inhibition. Given that contact inhibition is reversible, we predicted that mTOR is inhibited. In fact, we found that mTORC1 targets are dephosphorylated in contact inhibited cells. Furthermore, activation of mTOR shifts reversible contact inhibition towards senescence. Thus, it is deactivation of mTOR that suppresses geroconversion in contact inhibited cells. Deactivation of mTOR was associated with induction of p27. In cancer cells, there is no induction of p27 in high cell density. Accordingly, cancer cells do not get arrested in confluent cultures.

There is a complex relationship between p27 and mTOR. It turned out that the mTOR pathway was inhibited in dense cultures of cancer cells. Yet, cancer cells do not induce p27 and do not undergo contact inhibition. mTOR is constitutively activated in cancer and induction of p21 by itself does not inhibit mTOR. So why mTOR is deactivated not only in contact-inhibited but also in confluent cancer cells? The answer is that cancer cells with highly increased metabolism rapidly exhaust and acidify the medium, thus inhibiting mTOR by starvation-like mechanism. In fact, change of the medium restored mTOR activity. Therefore, in normal cells with low metabolism, mTOR is deactivated by contact inhibition and the change of the medium only marginally affects mTOR. In cancer cells, mTOR is inhibited due to exhaustion of the medium. And some cell lines are somewhere in between.

Link: http://www.impactaging.com/papers/v6/n12/full/100714.html

Comments

It would interesting to know if cell-to-cell gap junctions play a role.
They appear to be quite important in guiding cells through proper differentiation and avoiding unregulated cancerous growth.

Also, contact inhibition seems to play a role in maintaining tissue and extracellular matrix integrity in the naked mole rat -
"Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and
Anticancer Treatment"
http://www.karger.com/Article/FullText/362978
- cell-to-cell adhesion seems to promote gap junction formation

Posted by: Lou Pagnucco at January 12th, 2015 10:49 PM

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