Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer

Abstract

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

“…Studies found that 25% of patients with neuroblastoma showed an MYCN amplification and predicted poor prognosis independently of other factors ( Brodeur et al, 1984 ; Seeger et al, 1985 ). HSP90AA1 , one of the HSP90 isoforms, showed a significant correlation with survival time in lung cancer patients by inhibiting the AKT1 and ERK pathways ( Niu et al, 2021 ) and was upregulated in colorectal cancer ( Szczuka et al, 2021 ). HSP90 regulates the stability of MLKL and RIP3 and is required for TNF-stimulated necrosome assembly ( Zhao et al, 2016 ).…”

Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy

“…The serine/threonine kinase AKT (also known as PKB) controls key cellular processes such as proliferation and antiapoptotic effects. Inhibition of HSP90 downregulates the expression of Akt kinase and, as a result, sensitizes tumor cells to proapoptotic factors [ 31 , 32 ]. Focal adhesion kinase (FAK) and integrin-linked kinase (ILK) are critical promoters to cell adhesion.…”

HSP90 mediates the connection of multiple programmed cell death in diseases

“…Compared with normal tissue, cancer cell shows a higher expression of HSP90 on mRNA and protein level [ 49 ]. It was reported that the concentration of HSP90 in plasma is associated with the malignant degree of the tumor, which is supported by the clinical data of more than 4000 patients with breast cancer [ 50 ].…”

“…Some clients may mutate or overexpress in pathological cells, which is alleviated by HSP90 inhibitors, indicating a therapeutic role in cancer. The cancer-related clients, including mitogen-activated protein kinase (MAPK) kinase, extracellular signal-regulated kinase (Erk) 1/2, and Akt [ 49 , 51 ], take part in the proliferation, invasion and resistance of cancer cells [ 49 , 52 , 53 ]. For example, A synthetic inhibitor PF-4942847 exerts intensive effects on the viability of cancer cells by inducing apoptosis, delaying OS tumor growth and reducing lung metastasis [ 54 ].…”

“…Classical inhibitor GA has been reported that can induce autophagy and apoptosis in osteosarcoma cells by inhibiting the Akt signaling pathway [ 57 ]. Inhibitor 17-DMAG regulates the phosphorylation of Akt and Bcl-xl to increase apoptosis by targeting HSP90 whether in human or mouse lung cancer cells [ 49 ]. In addition, necroptosis is also an optional pathway for HSP90 inhibitor, which is related to the RIP1/RIP3/ mixed lineage kinase domain-like protein (MLKL) cascade [ 58 ].…”