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Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapyinduced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirininduced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.

BackgroundHumanized mouse models are still under development, and various protocols exist to improve human cell engraftment and function. MethodsFourteen NOD/SCID/IL-2Rnull (NSG) mice (4-5 wk old) were conditioned with busulfan and injected with human umbilical cord blood (hUCB)-derived CD34 + hematopoietic stem cells (HSC) via retro-orbital sinuses. The bone marrow (BM), spleen, and peripheral blood (PB) were analyzed 8 and 12 weeks after HSC transplantation. + T cells were barely detectable, while hCD7 + was detected in the BM and spleen. The percentage of hCD3 + T cells was 2-3% at week 12 in the BM, spleen, and PB of humanized NSG mice. Results Most of the ConclusionWe adopted a simplified protocol for establishing humanized NSG mice. We observed a higher engraftment rate of human CD45 + cells than earlier studies without any significant toxicity. And human CD45 + cell engraftment at week 8 was comparable to that of week 12.

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