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Caenorhabditis elegans Aging is Associated with a Decline in Proteostasis
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
In addition to genome-wide screens, a handful of targeted RNAi studies have been performed. For example, a candidate screen for molecular chaperons was performed on temperature-sensitive mutants as folding sensors. Molecular chaperones were identified that are specifically required for C. elegans muscle homeostasis [85]. Specifically, Hsp90 and its co-chaperones Sti-1, Aha1, and Cep23 were identified [85].
Bufalin serves as a pharmaceutic that mitigates drug resistance
Published in Drug Metabolism Reviews, 2023
Linxuan Miao, Ying Liu, Nasra Mohamoud Ali, Yan Dong, Bin Zhang, Xiaonan Cui
Gu et al. newly discovered that AHSA1 may be a new target for BF treatment of multiple myeloma (MM) (Chunyan et al. 2022). BF inhibited CDK6 and PSMD2 through specific binding to AHSA1-K137, abolishing the proteasome inhibitor (PI) resistance induced by AHSA1 in vitro and in vivo, and inhibiting tumor cell proliferation. In addition, it is well known that the TME plays a crucial role in the occurrence and development of cancer, and macrophages are even more ‘powerful’ in the TME. The increasing number of M2 macrophages may indicate that tumor cells are resistant to chemotherapy. A study confirmed that BF can reduce M2 macrophage polarization through the SRC-3/MIF pathway to reverse the chemoresistance of colorectal cancer in vivo (Chen et al. 2021). In addition, Na+/K + ATPase3 may serve as a therapeutic target of BF in hepatocellular carcinoma (HCC), and its expression status may contribute to the sensitive prediction of HCC cells on BF treatment (Li et al. 2011). These pathways may also be involved in their mechanisms of reversing drug resistance.
HSP90 and Co-chaperones: Impact on Tumor Progression and Prospects for Molecular-Targeted Cancer Therapy
Published in Cancer Investigation, 2020
Ameneh Jafari, Mostafa Rezaei-Tavirani, Behrouz Farhadihosseinabadi, Shahrouz Taranejoo, Hakimeh Zali
Along with other chaperones, HSP90 involved in the stabilization and maturation of a large number of client proteins, from folding and stress regulation to DNA repair, immune response, and many other processes (28). Client proteins including transcription factors [(HIF1 (Hypoxia-inducible factor 1), TP53)], receptor tyrosine kinases (HER2, EGFR, IGF-1R, MET), cell cycle regulatory proteins (CDK4, CDK6), and signaling proteins (AKT, SRC) (29–31). HSP90 requires several co-chaperones (e.g., p50/Cdc37, HSP90-organizing protein (HOP/Sti1, p23, Aha1, HSP70) and a variety of immunophilins to function (32,33). Hsp90 family members with intrinsic ATPase activity interact with a diversity of intracellular client proteins involved in cell growth, development, differentiation, and survival, which facilitates their protein homeostasis (proteostasis) (34,35). Proteostasis, including protein folding, client protein maturation, and protein trafficking, is critical for the survival of cells in physiological and pathological conditions (34,35).
An updated patent review of anticancer Hsp90 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Li Li, Nan-Nan Chen, Qi-Dong You, Xiao-Li Xu
Hsp90-dependent client proteins are correctly folded and matured through the Hsp90 chaperone cycle. Hsp90 chaperone cycle consists of three critical steps [15]: the conformational transformation of Hsp90 homodimer controlled by ATP/ADP binding; the formation of a super complex with co-chaperones; the release of matured client protein. Initially, Hsp90 homodimer exists in an open conformation with dimerization at the C-terminal domains. Unfolded client proteins, Hsp70 and the stress-inducible 1/Hsp70-Hsp90 organizing protein (HOP) form a ternary complex for Hsp90 binding[16]. The C-terminus of Hsp90 interacts with HOP, and the client proteins transfer to the M-terminal domain waiting for the closed status of Hsp90 N-terminus. The conformation varying is driven by ATP/ADP cycle[17]. The activity of ATPase is regulated by the activator of Hsp90 ATPase-1 (Aha1), which promotes ATP hydrolysis on the Hsp90 N-terminal pockets leading to the closure of Hsp90 N-terminus[18]. During this period, some co-chaperones such as Cdc37 binding to Hsp90 N-terminus partially impact the ATP-binding time. After that, ATP transfers to ADP, leading to the closure of Hsp90N, which provokes the maturation of clients. Meanwhile, p23 interacts with Hsp90N sequentially to form a super hetero-protein complex to stabilize the closed conformation. Then, client proteins fold into active stereostructure mediated by Hsp90 chaperone with ATP hydrolysis in Hsp90N. Hsp90-bound ADP caused the open conformation of Hsp90 N-terminal, resulted in the release of matured client proteins and the disassociation of co-chaperones. Then the restored Hsp90 chaperone enters into the next cycle for client proteins folding. The understanding of the Hsp90 chaperone cycle provides the molecular biology basis for the development of Hsp90 inhibitors[19].