Rapamycin induces pluripotent genes associated with avoidance of replicative senescence

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2013-12, Vol.12 (24), p.3841-3851
• Main Authors: Pospelova, Tatyana V., Bykova, Tatiana V, Zubova, Svetlana G, Katolikova, Natalia V, Yartzeva, Natalia M, Pospelov, Valery A
• Format: Article
• Language: English
• Subjects: aging; Animals; Autophagy; Cell Culture Techniques; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Proliferation - drug effects; Cells, Cultured; Cellular Senescence - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; gerosuppression; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Karyotype; mTOR; Nanog Homeobox Protein; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; rapalogs; Rats; senescence; Sirolimus - pharmacology; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Telomerase - genetics; Telomerase - metabolism
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.27396

Primary rodent cells undergo replicative senescence, independent from telomere shortening. We have recently shown that treatment with rapamycin during passages 3-7 suppressed replicative senescence in rat embryonic fibroblasts (REFs), which otherwise occurred by 10-14 passages. Here, we further investigated rapamycin-primed cells for an extended number of passages. Rapamycin-primed cells continued to proliferate without accumulation of senescent markers. Importantly, these cells retained the ability to undergo serum starvation- and etoposide-induced cell cycle arrest. The p53/p21 pathway was functional. This indicates that rapamycin did not cause either transformation or loss of cell cycle checkpoints. We found that rapamycin activated transcription of pluripotent genes, oct-4, sox-2, nanog, as well as further upregulated telomerase (tert) gene. The rapamycin-derived cells have mostly non-rearranged, near-normal karyotype. Still, when cultivated for a higher number of passages, these cells acquired a chromosomal marker within the chromosome 3. We conclude that suppression mTORC1 activity may prevent replicative senescence without transformation of rodent cells.