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

Mengyuan Niu,Junaid Wazir,Hongwei Wang,Lulu Wei,Panpan Lian,Wenyuan Pu,Zhonglan Su,Ranran Wang,Chen Zhao,Li Li,Shiyu Song,Bin Zhang,Qian Gao,Renwei Lu

doi:10.3389/fphar.2021.724192

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.

Highlights

Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide (Torre et al, 2015; Wood et al, 2015)
To investigate the role of Heat shock protein 90 (HSP90) in lung cancer, the transcription levels of 3 HSP90 isoforms (AA1, AB1, B1) were compared between lung cancer and normal lung tissue in three microarray and one RNA sequencing datasets. These three isoforms of HSP90 are all significantly up-regulated in cancer tissues compared with normal lung tissues. They were positively correlated with each other (Figure 1B), only the higher expression of HSP90AA1 was significantly correlated with shortened overall survival time in three datasets, including TCGA, in which survival data was available (Figure 1C)
HSP90 was important in cancer cells for FIGURE 7 | 17-DMAG inhibited tumor growth and induced cell death in vivo

Summary

Introduction

Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide (Torre et al, 2015; Wood et al, 2015). Despite various therapeutic approaches, including chemotherapy, immune checkpoint inhibitors, targeted protein kinase inhibitors et al, the 5-years survival rate of late-stage tumors remains poor with approximately 15% (Novello et al, 2013; Park et al, 2014). Heat shock protein 90 (HSP90) is a chaperon protein that is highly conserved in various species across the different kingdoms (Chen et al, 2006). There are two major cytosolic isoforms of Targeting HSP90 Inhibits Lung Cancer. HSP90 plays a crucial role in maintaining cellular protein homeostasis by assisting other proteins in folding properly, stabilizing proteins against heat stress, and promoting protein degradation (Schopf et al, 2017)

Methods

Results

Conclusion