Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 197, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2021.111517
Keywords
Therapy-induced senescence; Colon cancer; Methotrexate; Antigen presentation; AP-1 transcription factor; beta-catenin
Categories
Funding
- National Science Center, Poland [UMO-2015/17/B/NZ3/03531]
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This study compared two senescent states of colon cancer cells in response to methotrexate exposure, showing upregulation of immunoproteasome subunit-coding genes and MHC-I-restricted antigen presentation as common features. Changes in NF-kappa B p65 level and AP-1-dependent transcription were observed, along with beta-catenin signaling deregulation. These findings have implications for senescence establishment and potential advantages for colon cancer treatment.
Reversible cellular senescence was demonstrated previously to constitute colon cancer cell response to methotrexate. The current study presents a comparison of two senescent states of colon cancer cells, arrested and reversing, resulting from respectively, 120 h exposure to the drug, and 48 h exposure followed by 96 h regrowth in drug-free media. The upregulation of immunoproteasome subunit-coding genes and the increase in human leukocyte antigen HLA-A/B/C membrane level indicated MHC-I-restricted antigen presentation as common to both senescent states. Nuclear factor NF-kappa B p65 level decreased and activating protein AP-1: c-Jun, Fra2 and JunB nuclear levels increased in both senescent cell populations. Notably, the increase in AP-1-dependent transcription occurred after 48 h exposure to methotrexate. beta-catenin nuclear level increased after 48 h exposure to the drug and remained as such only in senescence-arrested cells. beta-catenin level was found uncoupled from the protein phosphorylation status indicating the deregulation of beta-catenin signaling in colon cancer cells employed in the study. These findings carry implications for both, a general mechanism of senescence establishment and putative advantages for colon cancer treatment.
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