Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth

Abstract

HSP60 is a mitochondrial localized quality control protein responsible for maintaining mitochondrial function. Although HSP60 is considered both a tumor suppressor and promoter in different types of cancer, the role of HSP60 in human pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we demonstrated that HSP60 was aberrantly expressed in human pancreatic cancer tissues and cell lines. Analysis of the Cancer Genome Atlas database revealed that HSP60 expression is positively correlated with pancreatic cancer. Further, knockdown of HSP60 attenuated pancreatic ductal cancer cell proliferation and migration/invasion, whereas ectopic expression of HSP60 increased tumorigenesis. Using an in vivo tumorigenicity assay, we confirmed that HSP60 promoted the growth of pancreatic ductal cancer cells. Functional analyses demonstrated that HSP60 plays a key role in the regulation of mitochondrial function. Mechanistically, both HSP60 knockdown and oxidative phosphorylation (OXPHOS) inhibition by metformin decreased Erk1/2 phosphorylation and induced apoptosis and cell cycle arrest, whereas Erk1/2 reactivation with EGF promoted cell proliferation. Intriguingly, in vitro ATP supplementation partially restored Erk1/2 phosphorylation and promoted proliferation in PDAC cells with HSP60 knockdown and OXPHOS inhibition. These results suggest that mitochondrial ATP is an important sensor of Erk1/2 regulated apoptosis and the cell cycle in PDAC cells. Thus, our findings indicate for the first time that HSP60 may serve as a novel diagnostic target of human pancreatic cancer, and that inhibition of mitochondrial function using drugs such as metformin may be a beneficial therapeutic strategy targeting pancreatic cancer cells with aberrant function of the HSP60/OXPHOS/Erk1/2 phosphorylation axis.

Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells

“…In tumor cells, HSP60 and survivin are capable of forming complexes to reside in either the mitochondria or the cytosol for survivin stabilization [9,12]. Consistent with the finding on stabilization of survivin by HSP60, silencing of HSP60 results in a decline of survivin expression [8,9,12]. As such, many similar biofunctions exist between HSP60 and survivin.…”

“…Clinical studies indicate that high HSP60 expression is associated with shorter survival in patients with serous ovarian cancer and gastric cancer [4,5]. Accordingly, HSP60 has been proposed as a biomarker for tumor growth and progression in several cancers, including breast [6], head and neck [7], colorectal [2], and pancreatic [8] cancers. HSP60 is capable of regulating apoptosis of tumor cells through interaction with several anti-or pro-apoptotic regulators such as Bax, Bak, p21, p53, and survivin [9][10][11].…”

“…HSP60 is capable of regulating apoptosis of tumor cells through interaction with several anti-or pro-apoptotic regulators such as Bax, Bak, p21, p53, and survivin [9][10][11]. The silencing of HSP60 results in inhibition of cell proliferation and promotion of apoptosis in tumor cells, suggesting its pro-survival and anti-apoptotic functions [8,12,13]. Nevertheless, the function of HSP60, in particular, the cytosolic HSP60, on the regulation of apoptosis appears to be more complex.…”

Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives

“…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.…”

“…It supports mitochondrial protein folding and assists in proteolytic degradation of denatured or aberrantly folded proteins in an ATP-dependent fashion (Azem et al, 1995;Henderson et al, 2013). HSP plays numerous physiological roles but can also be pathogenic in various conditions, including cancer and neurodegenerative diseases (Cappello et al, 2008;Bross et al, 2012;Zhou et al, 2018). Recent reports highlight the role and implication of HSP60 in human cancer development and management whereby its targeting has revealed promising therapeutic outcomes (Pace et al, 2013;Li et al, 2014;Meng et al, 2018).…”