p21 is necessary for the beneficial effects of fasting during chemotherapy

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p21 is necessary for the beneficial effects of fasting during chemotherapyDear Editor, Short-term fasting (up to 48 hours) activates strong physiological and molecular responses [1].We and others showed a p53-independent transcriptional activation of the cell cycle inhibitor p21 upon fasting, most strongly in the liver, muscles, and many other tissues [2, 3].Studies with mice [4, 5] and human patients [6] have shown the beneficial effects of short-term fasting during anti-cancer chemotherapy treatments.The aim of this study was to clarify the role of p21 induction in the beneficial effects of combining fasting and chemotherapy.For this, we first used the human colon cancer cell lines RKO and HCT116 and the colon nontumoral cell line CCD-18Co.Sensitivity of colon cancer cells RKO and HCT116 to the chemotherapeutic agent oxaliplatin (50-100 μmol/L) was enhanced when cells were cultured in a short-term starvation (STS) mimicking medium, while non-tumoral CCD-18Co cells were protected from chemotherapy toxicity (Supplementary Figure S1).The detailed methods of this study can be found in the Supplementary Methods.We subjected p21-wild type (WT) and p21-knockdown (p21-KD) cells to oxaliplatin treatment with a normal or STS medium.STS and oxaliplatin single treatments induced p21 mRNA and/or protein in p21-WT cells, while p21 expression was very low in p21-KD cells.Oxaliplatin and STS combination resulted in the highest increase in p21 expression in both genotypes (Figure 1A and Supplementary Figure S2A-G).Combining STS with chemotherapy sensitized p21-WT tumor cells and protected p21-WT non-tumoral cells, and these STS effects were lost in p21-KD cells (Figure 1B and Supplementary Figure S2H-K).p53 protein levels, undetectable in CCD-18Co cells, followed a similar trend to p21 in HCT116

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