Andrographolide induces degradation of mutant p53 via activation of Hsp70

Abstract

The tumor suppressor gene p53 encodes a transcription factor that regulates various cellular functions, including DNA repair, apoptosis and cell cycle progression. Approximately half of all human cancers carry mutations in p53 that lead to loss of tumor suppressor function or gain of functions that promote the cancer phenotype. Thus, targeting mutant p53 as an anticancer therapy has attracted considerable attention. In the current study, a small-molecule screen identified andrographlide (ANDRO) as a mutant p53 suppressor. The effects of ANDRO, a small molecule isolated from the Chinese herb Andrographis paniculata, on tumor cells carrying wild-type or mutant p53 were examined. ANDRO suppressed expression of mutant p53, induced expression of the cyclin-dependent kinase inhibitor p21 and pro-apoptotic proteins genes, and inhibited the growth of cancer cells harboring mutant p53. ANDRO also induced expression of the heat-shock protein (Hsp70) and increased binding between Hsp70 and mutant p53 protein, thus promoting proteasomal degradation of p53. These results provide novel insights into the mechanisms regulating the function of mutant p53 and suggest that activation of Hsp70 may be a new strategy for the treatment of cancers harboring mutant p53.

Semisynthesis and Pesticidal Activities of Derivatives of the Diterpenoid Andrographolide and Investigation on the Stress Response of Aphis citricola Van der Goot (Homoptera: Aphididae)

“…Compound 1 was found to induce degradation of mutant p53 via activation of Hsp70 in PANC-1 cell (human pancreatic cancer) and HCT116 cell (human colorectal cancer). 48 In our experiment, it is noteworthy that compounds 1, IIe, and Vb upregulated Hsp70 expressions to 2.64, 2.49, and 6.87 folds, respectively, whereas the change of Hsp70 expressions for imidacloprid was not obvious. It indicated that Hsp70 was an important gene involved in stress response to andrographolide and its derivatives are exposed to A. citricola.…”

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches

“…As an extremely interesting multitarget diterpenoid lactones, in recent years, andrographolide has attracted considerable number of interests in the medicinal chemistry society with its potential multiple pharmacological activities such as antiinflammatory (Ding et al, 2017), antioxidant (Mussard et al, 2019; Zhang et al, 2020), anticancer (Farooqi et al, 2020; Sato et al, 2018; Zhang et al, 2017), antimicrobial (Gupta, Mishra, & Ganju, 2017; Panraksa, Ramphan, Khongwichit, & Smith, 2017; Shi et al, 2020; Srivastava, Garg, Srivastava, & Seth, 2021), antihyperglycemic (Su et al, 2020) and regulating blood lipid (Lin et al, 2018), immunoregulation (Zhang, Yang, Du, & Guo, 2020), improving memory impairment (Das, Mishra, Ganju, & Singh, 2017), as well as mitigating cartilage damage (Chen, Luo, & Chen, 2020) and so on (Figure 2). In view of the increasing awareness of the side effects of chemotherapy drugs, this medicinal ingredient may serve as one of the backbones for the treatment of related diseases in the future.…”

Exosomal p38 Mitogen-activated Protein Kinase Promotes Tumour Repopulation in TP53-mutated Bile Duct Cancer Cells

“…Exosome/cytosol markers were evaluated using mouse monoclonal antibody against programmed cell death 6 interacting protein (PDCD6IP, alias Alix) (clone 3A9; Cell Signaling Technology) and polyclonal antibodies against CD63 (Santa Cruz Biotechnology) and calnexin (Cell Signaling Technology). A mouse monoclonal TP53 antibody (clone DO-1) which reacts with TP53-R175H was obtained from Santa Cruz Biotechnology (25), and a mouse monoclonal antibody against β-actin was obtained from Sigma-Aldrich (St Louis, MO, USA). Following the reaction with horseradish peroxidase-conjugated secondary antibodies, blot signals were observed using an enhanced ECL Western blotting detection system (Cytiva, Uppsala, Sweden).…”