Trends in Biochemical Sciences
Heat shock proteins in cancer: chaperones of tumorigenesis
Introduction
Heat shock proteins (HSPs) are the products of several distinct gene families that are required for cell survival during stress and are named according to the approximate relative molecular mass (Mr) of their encoded proteins, including HSP10, HSP27, HSP40, HSP60, HSP70, HSP90 and HSP110 1, 2, 3, 4 (Table 1). The cytoprotective properties of the HSPs are closely linked to their primary functions as molecular chaperones 1, 5, 6. The intracellular reactions catalyzed by the HSPs, which led to their designation as molecular chaperones, are divided into two main categories described as ‘protein holding’ and ‘protein folding’ 7, 8.
The principal holding proteins belong to the HSP70 and HSP90 families, which bind to unfolded sequences in polypeptide substrates and show preference for hydrophobic regions 8, 9. Such holding interactions occur (i) during mRNA translation, when HSP70 binds to the elongating polypeptide chain to prevent premature self-associations in the nascent protein; (ii) during heat shock, when proteins partially unfold and expose hydrophobic sequences that are bound by an HSP; and (iii) constitutively, when HSP90 binds to proteins with unstable tertiary structures 8, 10. HSP70 and HSP90 function in large complexes or ‘chaperone machines’ containing several accessory proteins or co-chaperones that bind the primary chaperone to mediate substrate selection and cycles of association with, and disassociation from, the substrate 9, 10 (Table 1). After completion of their molecular chaperone function, HSP70 and HSP90 are actively released from protein substrates by means of their intrinsic ATPase domains [2].
Protein folding, which occurs after the holding proteins release their substrate, involves the HSP60 ‘chaperonin’ family and several other related chaperonin proteins 11, 12. Chaperonins self-associate to form large folding chambers in which the substrate protein can undergo the appropriate intramolecular interactions required to attain its correct tertiary structure in an ATP-dependent process 11, 12. These distinctions are not absolute, however, and HSP70 can mediate the folding of some substrates [9]. Protein folding also involves the HSP27 family, although these proteins use mechanisms that do not readily fit into this scheme; for example, the small HSPs assemble into large aggregates that mediate holding and folding in an ATP-independent manner [13].
In addition to this humble molecular chaperone role, the HSPs also have key functions in controlling cellular metabolism [10]. Cell regulation by molecular chaperones is mediated by the holding ability of HSP70 and HSP90, each of which can bind stably to several regulatory molecules [10]. As we describe later, HSP90 has a principal role in regulating mitogenesis and cell-cycle progression and HSP70 is closely involved in protection from programmed cell death (PCD), each through interactions with several key regulatory proteins (Figure 1, Figure 2).
These molecular chaperone properties are harnessed during heat shock, when numerous cellular proteins undergo synchronous unfolding owing to the chaotropic effects of heat and threaten the cellular catastrophe of protein aggregation [14]. Such protein aggregation is deterred by engagement of the heat-shock response and the accompanying abundant expression of the HSP cohort, which recognizes denatured proteins through the holding properties of HSP27, HSP70 and HSP90, and subsequently refolds them with the aid of chaperonins [15]. In addition, because protein denaturation and aggregation are powerful triggers of PCD, HSPs have developed powerful anti-apoptotic properties that deter PCD and thus permit a time window for subsequent repair of the proteome 6, 16. The massive upregulation of HSPs that occurs during heat shock involves facilitation of expression at every level, including activation of the potent heat-shock transcription factor 1 (HSF1), stabilization of HSP mRNA, selective translation of HSPs, and stabilization of HSPs at the protein level 1, 17.
As we discuss here, evolving studies indicate that these potent cytoprotective and folding properties of the HSPs are co-opted during malignant progression when the HSPs become expressed at high level to facilitate tumor cell growth and survival [18].
Section snippets
Essential steps in tumor progression
Most tumors are formed by a stepwise progression of cells from a transformed but minimally altered state that can grow and form nodules or polyps (in solid tumors) to a multiply deviated state that is capable of unlimited growth, manipulation of the local environment, invasion of surrounding tissues and escape into the circulation to found new colonies of secondary tumors or metastases. Such a progression involves diverse molecular and morphological changes.
In their landmark review, Hanahan and
HSP90 and self-sufficiency in growth signals
The effects of the HSPs on the anabolic pathways leading to the first of the essential alterations in the Hanahan and Weinberg scheme [19] – namely, self-sufficiency in growth signals – are mediated largely by HSP90. This molecular chaperone is indispensable for stabilizing the fragile structures of many of the receptors, protein kinases and transcription factors that lie along the pathways of normal cellular growth [22]. HSP90 is required to maintain signaling proteins in an active
Concluding remarks
In summary, HSPs are expressed in increased amounts in many cancers owing to the de-repression of their genes during malignant progression. At these high levels, HSP family members play an essential, facilitating role in cancer by permitting autonomous growth through the accumulation of overexpressed and mutated oncogenes and by inhibiting the PCD of tumor cells. The increased abundance of HSPs, however, also offers a tempting target for oncologists to design treatments that can inhibit broad
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