P53代表着在包括结肠直肠癌（CRC）在内的癌症中调控凋亡的关键因子。结肠直肠癌在全球癌症患病率和死亡统计中排名第三。虽然白藜芦醇对CRC细胞的促凋亡效应已被多次证实，但其途径机制尚不完全清楚，因为文献中关于其调控相互作用的蛋白Sirt-1和p53的激活或抑制存在争议。 结肠直肠癌细胞分为野生型（HCT-116 WT）和p53缺陷型（HCT-116 p53-/-），采用含有T淋巴细胞和成纤维细胞的多细胞肿瘤微环境（TME）培养进行培养，以阐明p53/Sirt-1调控对白藜芦醇浓度依赖性的促凋亡和抗癌作用。 白藜芦醇剂量依赖性地抑制HCT-116 WT细胞的存活、增殖、可塑性和迁移，并在HCT-116 p53-/-细胞中的效果要比HCT-116 WT细胞更低。此外，当白藜芦醇在低浓度（<5µM）添加到CRC-TME中时，它能够刺激Sirt-1的表达，但当其在高浓度（>10µM）添加到CRC-TME中时，会抑制Sirt-1的表达。同时，在mRNA水平上抑制Sirt-1的处理和高浓度白藜芦醇的处理促使p53的乙酰化、p21、Bax、细胞色素C、半胱天冬酶-3的表达，并最终诱导CRC WT细胞的凋亡，而在CRC p53-/-细胞中没有这种效果。值得注意的是，白藜芦醇浓度的增加会促进p53和FOXO3a的过转录后翻译乙酰化，显示出Sirt-1和p53之间的负调控环。 这些结果首次证明了p53和Sirt-1在白藜芦醇浓度较高时在CRC-TME中的负相互作用，从而诱导凋亡。 版权所有 © 2023 Brockmueller, Buhrmann, Shayan and Shakibaei.

P53 represents a key player in apoptosis-induction in cancers including colorectal cancer (CRC) that ranks third worldwide in cancer prevalence as well as mortality statistics. Although a pro-apoptotic effect of resveratrol has been repeatedly proven in CRC cells, its pathway mechanisms are not completely understood, as there are controversial statements in the literature regarding its activation or inhibition of the counteracting proteins Sirt-1 and p53.CRC cells as wild-type (HCT-116 WT) or p53-deficient (HCT-116 p53-/-) were cultured using multicellular tumor microenvironment (TME) cultures containing T-lymphocytes and fibroblasts to elucidate the role of p53/Sirt-1 modulation in resveratrol's concentration-dependent, pro-apoptotic, and thus anti-cancer effects.Resveratrol dose-dependently inhibited viability, proliferation, plasticity as well as migration, and induced apoptosis in HCT-116 WT more effectively than in HCT-116 p53-/- cells. Moreover, resveratrol stimulated Sirt-1 expression when administered at low concentrations (<5µM) but suppressed it when added at high concentrations (>10µM) to CRC-TME. In parallel, similar to the knockdown of Sirt-1 at the mRNA level, treatment with high-concentration resveratrol boosted the acetylation of p53, the expression of p21, Bax, cytochrome C, caspase-3, and ultimately induced apoptosis in CRC WT but not in CRC p53-/- cells. Notably, increasing concentrations of resveratrol were found to promote hyperacetylation of p53 and FOXO3a as post-translational substrates of Sirt-1, indicating a negative regulatory loop between Sirt-1 and p53.These results demonstrate for the first time, a negative reciprocal crosstalk between the regulatory circuits of p53 and Sirt-1, consequently, apoptosis induction by higher resveratrol concentrations in CRC-TME.Copyright © 2023 Brockmueller, Buhrmann, Shayan and Shakibaei.