Senescence and Hypoxia Regulate Colon Cancer Cell Transcriptome and Secretome: Insights into Cancer Cell Senescence Pathophysiology

We investigated the effects of senescence and hypoxia on the transcriptome and secretome of the colon cancer cell, HCT-116, in an in vitro model. Senescence was confirmed using SA-β Gal staining and the expression of p53 and p21 proteins, and hypoxia using HIF-1α protein. Control (CN) and senescent (SN) cells were exposed to normoxia or hypoxia, control hypoxia (CH), and senescent hypoxia (SH). Senescence (SN, SH) enhanced the expression of kallikrein-related peptidases, TPp53, p21, optineurin, lipocalin, ADH-1, and stratifin by several folds. Stratifin, with tumor suppressive functions, was upregulated in senescent cells under normoxia but not in hypoxia. Hypoxia (CH and SH) upregulated the expression of many glycolysis genes, especially HK, PFK, aldolase, PDH kinase, and LDH-A. Mitochondrial RNAs (tRNA and rRNA) were increased in SH compared to CH. Significant increases in the secretion of IL-1α, endothelin, bFGF, HB-EGF, PDGF-AB, CCL-5, 7, 22, and CXCL-1 and 8 were observed in SN and SH. VEGF-A, VEGF-C, and TNF-β secretion increased, while PLGF, TGF-α, IL-27, GM-CSF, and M-CSF decreased under hypoxic (CH and SH) conditions. Thus, senescence and hypoxia contribute to cancer cell senescence pathophysiology by regulating the cellular transcriptome and secretome and by both positive and negative feedback mechanisms.