Chaperome Networks - Redundancy and Implications for Cancer Treatment

Abstract

The chaperome is a large family of proteins composed of chaperones, co-chaperones and a multitude of other factors. Elegant studies in yeast and other organisms have paved the road to how we currently understand the complex organization of this large family into protein networks. The goal of this chapter is to provide an overview of chaperome networks in cancer cells, with a focus on two cellular states defined by chaperome network organization. One state characterized by chaperome networks working in isolation and with little overlap, contains global chaperome networks resembling those of normal, non-transformed, cells. We propose that in this state, redundancy in chaperome networks results in a tumor type unamenable for single-agent chaperome therapy. The second state comprises chaperome networks interconnected in response to cellular stress, such as MYC hyperactivation. This is a state where no redundant pathways can be deployed, and is a state of vulnerability, amenable for chaperome therapy. We conclude by proposing a change in how we discover and implement chaperome inhibitor strategies, and suggest an approach to chaperome therapy where the properties of chaperome networks, rather than genetics or client proteins, are used in chaperome inhibitor implementation.

Keywords: Anti-cancer therapy; Chaperome networks; Epichaperome; HSP90 inhibitors; PU-H71; Protein network connectivity; Protein network vulnerability.

Fig. 6.1. Cancer cells with a global chaperome network composed of insular, partly overlapping, chaperome networks.

(a) Fluctuations in the cellular environment are rapidly dispersed, and cellular function stabilized, by network rearrangement and workload transfer among networks. (b) The temporary impairment of a sub-network by drugs can be rescued by alternate subnetworks coming into play to take over the workload of the impaired chaperome. Cellular survival is maintained and cells recover after drug removal

Fig. 6.2. Cancer cells with a highly interconnected global chaperome network.

Certain cancer cells characterized by large proteome imbalances (such as induced by MYC hyperactivation) rewire individual chaperome networks into a hyperconnected cellular network, the epichaperome. Inhibition of key nodes in the epichaperome network propagates to the entire network and results in overall network collapse. Cells cannot survive epichaperome collapse and cell death ensues

Fig. 6.3

Paradigm for a chaperome network-driven approach to cancer therapy