Clostridioides difficile Toxin B Induced Senescence: A New Pathologic Player for Colorectal Cancer?

Abstract

Clostridioides difficile (C. difficile) is responsible for a high percentage of gastrointestinal infections and its pathological activity is due to toxins A and B. C. difficile infection (CDI) is increasing worldwide due to the unstoppable spread of C. difficile in the anthropized environment and the progressive human colonization. The ability of C. difficile toxin B to induce senescent cells and the direct correlation between CDI, irritable bowel syndrome (IBS), and inflammatory bowel diseases (IBD) could cause an accumulation of senescent cells with important functional consequences. Furthermore, these senescent cells characterized by long survival could push pre-neoplastic cells originating in the colon towards the complete neoplastic transformation in colorectal cancer (CRC) by the senescence-associated secretory phenotype (SASP). Pre-neoplastic cells could appear as a result of various pro-carcinogenic events, among which, are infections with bacteria that produce genotoxins that generate cells with high genetic instability. Therefore, subjects who develop IBS and/or IBD after CDI should be monitored, especially if they then have further CDI relapses, waiting for the availability of senolytic and anti-SASP therapies to resolve the pro-carcinogenic risk due to accumulation of senescent cells after CDI followed by IBS and/or IBD.

Role of the Alteration in Calcium Homeostasis in Cell Death Induced by Clostridioides difficile Toxin A and Toxin B

“…[48,[113][114][115][116]138] Intercellular junctions are targets of Tcds Refs. [8][9][10][11]60,164,[168][169][170][171][172][173][174][175] Abbreviations: pore-forming toxins (PFTs); Clostridioides difficile (C. difficile) toxins (Tcds); calcium (Ca 2+ ); frizzled proteins (FZDs); inositol triphosphate (IP3); nicotinic acid adenine dinucleotide phosphate (NAADP); triphosphate receptor (IP3R); protein kinase C (PKC).…”

“…TcdA and TcdB, after binding to the cell plasma membrane receptors for Tcd, prompt its uptake by different pathways. Uptake of TcdB is mediated by clathrin, while that of TcdA is mediated by PACSIN2/syndapin-II [ 8 , 59 , 60 ]. Following Tcd uptake in the endocytic vacuole, the increase in pH acidity elicits conformational modifications of Tcd that promote the insertion of catalytic domain of Tcds externally to the membrane for its cleavage favored by the cell’s IP6 and translocation into the cytoplasm.…”

“…Following Tcd uptake in the endocytic vacuole, the increase in pH acidity elicits conformational modifications of Tcd that promote the insertion of catalytic domain of Tcds externally to the membrane for its cleavage favored by the cell’s IP6 and translocation into the cytoplasm. Then, Tcds glucosylate Rho-GTPase at the catalytic site, inhibiting their functions [ 8 , 9 , 10 , 11 , 60 ]. Glucosylation of Rho-GTPase induces several important biological effects, such as [ 8 , 9 , 10 , 11 , 12 , 46 , 60 , 61 ]: (1) early cytoskeletal alteration, dismantlement of focal adhesion and tight-junction disruption, which in vitro result in cell rounding (cytopathic effect); (2) cell cycle arrest, associated with reduced expression of the cyclin D1/Cdk4 or cyclin B1/Cdk1 complex, which are required for progression by the G1 or G2 phase, respectively, resulting in G1/S or G2/M arrest; and (3) cell death (cytotoxic effect), which occurs after the cycle arrest, mainly by apoptosis and necrosis, though it may also occur by pyknosis or pyroptosis.…”

“…Studies on the mechanisms by which TcdA [ 66 , 83 , 84 , 85 , 86 , 87 ] or TcdB [ 46 , 47 , 72 , 88 , 89 , 90 , 91 , 92 ] induces apoptosis have shown a central role played by caspases. In fact, it has been demonstrated in several different cell types that the executioner caspase-3 plays a key role in TcdA- and TcdB-induced apoptosis [ 8 , 9 , 10 , 11 , 46 , 47 , 60 ] but activation of the executioners caspase-6 and caspase-7 was also involved [ 46 , 47 , 60 , 66 , 85 ].…”

“…Tcds are capable of inducing apoptosis [ 8 , 9 , 10 , 11 , 46 , 47 , 60 ] through a mitochondrial pathway and cytochrome C release, which activates caspase-9 and the executioner caspases (caspase-3, caspase-6 and caspase-7) [ 46 , 47 , 66 , 85 , 86 , 87 , 93 , 94 , 102 , 103 ]. Tcds are also able to induce apoptosis by activated calpains, with effector expression in caspases [ 47 , 86 ].…”