Cytosolic Hsp60 Is Involved in the NF-κB-Dependent Survival of Cancer Cells via IKK Regulation

Abstract

Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-α-mediated activation of the IKK/NF-κB survival pathway via direct interaction with IKKα/β in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-κB activation and the expression of NF-κB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-α. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-κB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-κB pathway.

Isoledene from Mesua ferrea oleo-gum resin induces apoptosis in HCT 116 cells through ROS-mediated modulation of multiple proteins in the apoptotic pathways: A mechanistic study

“…This reduction is HSPs is suggested to contribute in IR-SF-mediated down-regulation of survivin. An inverse relationship between intracellular ROS levels and expression of HSP27, HSP60 and survivin has been highlighted by numerous studies (Chun et al, 2010;Pathi et al, 2012;Vidyasagar et al, 2012). Dose-dependent up-regulation of ROS in IR-SF treated cells together with above mentioned findings suggest that ROS is playing a major role in IR-SF-induced apoptosis in HCT 116 cells.…”

HSP60 Predicts Survival in Advanced Serous Ovarian Cancer

“…The mechanisms by which HSP60 mediates the observed poor prognosis and treatment resistance remain unclear, but likely include antiapoptotic and prosurvival features. 6,7,11,12 Increased HSP60 mRNA and protein levels have, in ovarian cancer cell lines, been correlated with platinum resistance. 28Y30 This increase does not seem to be associated with gene amplification, 28 so plausible mechanisms could be increased mRNA stability or transcriptional activity.…”

“…9,10 Heat shock protein 60 can associate with survivin and impede p53 function, 6 and in a multichaperone complex together with HSP90 and tumor necrosis factor receptorYassociated protein 1 (TRAP1), HSP60 can inhibit mitochondrial permeability transition and caspase-dependent apoptosis. 7 Furthermore, HSP60 activates the nuclear factor J# survival pathway 11,12 and has been shown to interact with A-catenin in promoting metastasis. 13 Given their role in promoting cell survival, HSPs have been studied in cancer and associated with poor survival in several cancer types, such as breast, endometrial, colon, and prostate cancer.…”

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

“…5D). The increased acetylation on these ETC subunits and Hsp60 in Sirt3 KO mitochondria suggests that they are direct substrates of Sirt3 and that changes in their acetylation status contribute to the altered the generation of mitochondrial ROS and response to oxidative stress (28)(29)(30).…”