HSP60-regulated Mitochondrial Proteostasis and Protein Translation Promote Tumor Growth of Ovarian Cancer

Abstract

Ovarian cancer (OC) is the most lethal gynecological carcinoma due to the lack of diagnostic markers and effective drug targets. Discovery of new therapeutic targets in OC to improve the treatment outcome is urgently needed. We performed proteomic analysis of OC specimens and the paired normal tissues and revealed that proteins associated with mitochondrial proteostasis and protein translation were highly expressed in ovarian tumor tissues, indicating that mitochondria are required for tumor progression of OC. Heat shock protein 60 (HSP60), an important mitochondrial chaperone, was upregulated in ovarian tumors. HSP60 silencing significantly attenuated growth of OC cells in both cells and mice xenografts. Proteomic analysis revealed that HSP60 silencing downregulated proteins involved in mitochondrial functions and protein synthesis. Metabolomic analysis revealed that HSP60 silencing resulted in a more than 100-fold increase in cellular adenine levels, leading to increased adenosine monophosphate and an activated AMPK pathway, and consequently reduced mTORC1-mediated S6K and 4EBP1 phosphorylation to inhibit protein synthesis that suppressed the proliferation of OC cells. These results suggest that HSP60 knockdown breaks mitochondrial proteostasis, and inactivates the mTOR pathway to inhibit OC progression, suggesting that HSP60 is a potential therapeutic target for OC treatment.

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…At the same time, HSP60 may function as a promoter and suppressor of cancer formation depending on disease type. In ovarian cancer (OC), the increased expression of HSP60 enhances tumor progression by stabilizing mitochondrial homeostasis and activating mTOR signaling pathway [34]. In glioblastoma, inhibition of HSP60 leads to the increased formation of reactive species (ROS) in mitochondria, subsequently exerting the complex I inhibitor retenone-induced AMPK activation, which in turn suppresses mTORC1-mediated phosphorylation of S6K and 4EBP1 and deactivates the protein translation machinery and cancer cell growth [33].…”

Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives

“…In human cancer HeLa cells, cytosolic HSP60 has been shown to support nuclear factor-kB (NF-kB)-dependent survival through binding and regulating the activity of IkB kinase (IKK) (Chun et al, 2010). Moreover, HSP60 knockdown in ovarian cancer cells inhibits tumor progression by breaking mitochondrial proteostasis, and inactivating the mTOR pathway (Guo et al, 2019). With regard to cancer metastasis, HSP60 has been described as a key chaperone that promotes metastatic phenotypes both in vitro and in vivo (Tsai et al, 2009).…”

“…Recent reports highlight the perspectives of targeting HSP60 as a future tool for cancer treatment (Nakamura and Minegishi, 2013;Cappello et al, 2014;Meng et al, 2018). In fact, HSP60 inhibition has been implemented as a therapeutic strategy in various types of cancers including melanoma (Kamm et al, 2019), pancreatic cancer (Zhou et al, 2018), and ovarian cancer (Guo et al, 2019). However, few reports concerned its targeting in HCC.…”

“…HSP60 has been studied as biomarker for diagnosis and prognosis assessment and as therapeutic agent in a range of diseases, such as gastric (Li et al, 2014), bronchial (Cappello et al, 2005), colorectal (Hamelin et al, 2011) and ovarian cancer (Guo et al, 2019), as well as glioblastoma (Khalil and James, 2007) and esophageal squamous cell carcinoma (Faried et al, 2004). Nevertheless, the role of HSP60 in HCC remains poorly understood.…”

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

“…The impacts of HSP60 on AMPK activity is controversial. In cancer cells, HSP60 silencing can activate AMPK through triggering the excessive ROS production, which is beneficial for tumor progression [39,40]. In adipose tissues, however, high-fat diet feeding induces a reduction of HSP60 protein levels and this change is not associated with any changes in AMPK activity [41].…”