Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Olga V. Leontieva, Zoya N. Demidenko, and Mikhail V. Blagosklonny

Significance

This work solves longstanding mysteries in the field of contact inhibition (CI), cancer, and aging. As shown here during CI, cells do not undergo senescence, thus resuming proliferation after replating. We found that CI was associated with inhibition of the mammalian target of rapamycin (mTOR) pathway, which is required for the senescence program. In cancer cells, lacking CI, mTOR was still inhibited in high cell density by an alternative mechanism. Our work explains why CI is reversible and how cells can avoid senescence in vivo, allowing the organism to last for decades. Implications for cancer therapy are discussed.

Abstract

During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR. Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence. Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.https://www.pnas.org/content/early/2014/05/29/1405723111

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https://www.ncbi.nlm.nih.gov/pmc/journals/1558/
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and completed by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
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https://www.scientificamerican.com/article/a-new-path-to-longevity/