Hsp60 expression, new locations, functions, and perspectives for cancer diagnosis and therapy

Abstract

Hsp60 in eukaryotes is considered typically a mitochondrial chaperone (also called Cpn60) but in the last few years it has become clear that it also occurs in the cytosol, the cell surface, the extracellular space, and in the peripheral blood. Studies with prokaryotic models have shown that Hsp60 plays a role in assisting nascent polypeptides to reach a native conformation, and that it interacts with Hsp10 (which also resides in the mitochondria and is also named Cpn10). In addition to its role in polypeptide folding in association with Hsp10, other functions and interacting molecules have been identified for Hsp60 in the last several years. Some of these newly identified functions are associated with carcinogenesis, specifically with tumor cell survival and proliferation. Thus, assessing the levels of Hsp60 in tumor cells and in sera of cancer patients is becoming an attractive area of investigation aiming at the development of means for practical applications in clinical oncology. Since Hsp60 participates in extracellular molecular interactions and cell signalling and also in key intracellular pathways of some types of tumor cells, the idea of using Hsp60 in anti-cancer therapy (chaperonotherapy) is being investigated. The Hsp could be used either as an anticancer agent alone or in combination with tumor antigens, or as target for anti-chaperone compounds. In this article, a brief review is presented of representative research efforts aimed at assessing Hsp60 in a variety of tumors with the purpose of illustrating possible implications and applications for making early and differential diagnoses, assessing prognosis, monitoring response to treatment, and for developing novel anti-cancer strategies.

Upon oxidative stress, the antiapoptotic Hsp60/procaspase-3 complex persists in mucoepidermoid carcinoma cells

“…Hsps form an ancient anti-stress, defence system in all living organisms on earth, mediating a wide range of intracellular activities, and their expression can be induced by a variety of stressors including apoptotic stimuli. Hsp60 is a chaperonin localized to the inner mitochondrial membrane and C. Campanella et al matrix and, less frequently, to extramitochondrial sites (Soltys and Gupta, 1996, 1997Cappello et al, 2008). Hsp60 is constitutively expressed under normal conditions, but its levels can increase (as determined by immunohistochemical methods for example) in pre-neoplastic lesions (Cappello et al, 2002(Cappello et al, , 2003a(Cappello et al, , 2003bFan et al, 2006) and in many advanced cancers (Schneider et al, 1999;Cappello et al, 2005;Urushibara et al, 2007).…”

“…Hsp60, including probably the mitochondrial Cpn60, can be elevated in a number of human tumors (Czarnecka et al, 2006;Cappello et al, 2007;2008) and in the extracellular milieu, which can cause activation of an antitumor immune response (Calderwood et al, 2007). Whether and when mitochondrial and cytosolic Hsp60 have pro-or anti-apoptotic roles is still unclear, since there is evidence supporting both possibilities (Samali et al, 1999;Xanthoudakis et al, 1999;Gupta et al, 2005;Veereshwarayya et al, 2006;Chandra et al, 2007).…”

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex ( CubipyOXA ) leads to cell death in NCI-H292 cancer cells

“…The molecular chaperone Hsp60 assists protein folding in prokaryotes and in eukaryotic cells in order to maintain protein homeostasis and tissue physiology [4]. Hsp60 has been implicated in carcinogenesis via its interaction with components of the Caspase cascade that leads to apoptosis.…”

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

“…Moreover, the decrease of the intracellular levels of the chaperonin may lead to a decrease in its extracellular release. Extracellular chaperones contribute to the intercommunication between different cells, tissues, and organs, in normal as well as in pathological conditions [18,63].…”

“…In fact, specific down-regulation of Hsp70 leads to rapid senescence of various cancer cell lines [15], and human neuroblastoma cells displayed senescence-like characteristics after inhibition of Hsp90 with tanespimycin (17AAG) [16]. The mitochondrial chaperonin Hsp60 also named HSPD1 [17] was found in multiple subcellular sites and function in the folding and intracellular trafficking of many proteins [18,19]. Hsp60 has been found elevated in a large number of human carcinomas, which opens novel perspectives for cancer diagnosis and therapy targeting Hsp60 [20,21].…”