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Hikeshi is a protein that mediates the heat stress-induced nuclear import of heat shock protein 70 (HSP70: HSPA1 and HSPA8). Dysfunction of Hikeshi in humans can cause serious hereditary diseases, but the cellular function of Hikeshi is not fully understood. Previously, we reported that depletion of Hikeshi resulted in different effects in two human cell lines following proteotoxic stress. Depletion of Hikeshi reduced the survival of HeLa cancer cells after proteotoxic stress. However, Hikeshi-knockout (KO) hTERT-RPE1 cells, immortalized with telomerase reverse transcriptase, acquired resistance against proteotoxic stress, which was accompanied by increased p21 (WAF1/CIP1, CDKN1A) expression. p21 is a cell-cycle inhibitor and a direct p53-regulated target gene. Here, we investigated the effect of Hikeshi depletion and inhibition of HSP70 molecular chaperone function on cellular signaling in HeLa and hTERT-RPE1 cells. Functional modulation of HSP70 with the inhibitor YM-1 caused cell death in the HeLa cells but resulted in growth arrest of the hTERT-RPE1 cells. Further, YM-1 treatment dramatically up-regulated p53 and p21 proteins in hTERT-RPE1 cells and down-regulated FoxM1 and survivin, which are regulators of cell cycle progression, in both hTERT-RPE1 cells and HeLa cells. Our results showed that regardless of the presence or absence of Hikeshi, the p53-p21 pathway becomes active when hTERT-RPE1 non-cancer cells are treated with YM-1, which contributes to protection against cell death. Hikeshi might function as an upstream regulator of HSP70, which affects activation of the p53-p21 pathway, especially during and after proteotoxic stress.