Grp94 Inhibitor HCP1 Inhibits Human Dermal Fibroblast Senescence

Abstract

Researchers are paying more and more attention to aging, especially skin aging. Therefore, it is urgent to find an effective way to inhibit aging. Here, we report a small chemical molecule, HCP1, that inhibited the senescence of human dermal fibroblasts (HDFs). First, we performed morphological experiment and found that HCP1-treated HDFs were no longer elongated and flat compared to DMSO-treated groups. Next, we found that the number of β-gal positive cells decreased compared to DMSO-treated groups. Through flow cytometry, western blot, and immunofluorescence, we found that HCP1 could inhibit the senescence of HDFs. In the study of the mechanism, we found that HCP1 could regulate the AMPK/mTOR signal pathway through glucose-regulated protein 94 (Grp94). In addition, we found that HCP1 could promote the interaction between Grp94 and lysosomes, which led to an increase in the activity of lysosomes and inhibited the senescence of HDFs. At the same time, we found that HCP1 decreased the concentration of Ca2+ in mitochondria, inhibiting the senescence of HCP1. Therefore, we propose that HCP1 is a potential aging-inhibiting compound, and provide a new idea for the development of senescence-inhibiting drugs.

Inhibition of annexin A7 suppresses senescence‐associated heterochromatin foci formation and senescence through the AMPK/mTOR pathway in human dermal fibroblasts

“…Our experiment results of these research showed that during inhibiting SAHF formation, ANXA7 mainly worked in the nucleus, while Grp94 did not translocate into the nucleus, it worked in the cytoplasm. 36 The results of our laboratory showed that either high or low phosphorylation of the Ser93 site of HP1γ could inhibit the formation of SAHF in dermal fibroblasts, and the detailed molecular mechanism needs to be further studied. In addition, the different site phosphorylation of HP1γ might take place in different cellular locations.…”

Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice

“…Another key senescence-promoting marker that we identified was heat shock protein Hsp901b (aka Grp94), which was significantly elevated (319%, q = 0.003) in 25-mth-old mice. This Hsp901b has received much recent attention as a target to inhibit to prevent senescence in humans ( Cui et al, 2022 ) and positively correlates ( p < 0.05) with upregulated expression of IL-18 (an NLRP3 inflammasome cytokine) in our 25-mth-old colon cells. Finally, p21 ( Cdkn1a ) gene expression loss strongly positively correlated (R > 0.5, q < 0.05) with expression losses of multiple genes, including Ctnnb1 and Hmgb1 , as well as increased abundances in several Gn genera ( Figure 6C ).…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Radiation-induced senescence involves increased autophagy in lung cancer cells [ 18 ]. Senescent cells appear large, flattened, and irregularly shaped, which is attributed to increased mammalian target of rapamycin (mTOR) signaling [ 111 , 112 ]. Derivatives of indolo [2,3-a]pyrrolo [3,4-c]carbazole induce senescence by modulating AKT/mTOR/S6K signaling in breast cancer cells, lung cancer cells, and colon cancer cells [ 112 ].…”