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

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

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

oncotarget research
When general population speak of modern medicine, accuracy plays one of the most important roles and human lives are directly dependent on it. Likewise, any researches pertaining to medicine are required to comply with the highest standards. The issue nowadays is that any recommendations of researches can be shared online and used as a reference without being precisely checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this issue and attempted to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The key principle of this journal is related to Altmetric scores that are used as a quality indicator. That assists both readers and authors to quality-check publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a complete publications list with respective scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it creates the required assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and completed by different 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.”
The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Likewise, the publication about melanoma, was used for citations in different news articles 69 times. Moreover, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get helpful scientific facts. Oncotarget is glad to have the ability to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
https://soundcloud.com/oncotarget

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