Adapting to stress — chaperome networks in cancer

Abstract

In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

Therapeutic targeting of cellular stress responses in cancer

“…Single‐celled organisms, including bacteria and yeast, have developed mechanisms to survive in the face of environmental stresses by promoting mutagenesis, thereby increasing genetic diversity . These adaptations involve increased genomic instability and mutation, coupled with changes to signaling pathways and gene expression programs, creating an intricate network that researchers have been trying to unravel in recent years . Uncovering the molecular mechanisms by which plants and microorganisms respond to stresses will help us to better understand biological evolution .…”

HSP90 facilitates oncogenic alterations of metabolism in B-cell lymphomas

“…Taking advantage of our methodology to isolate native proteins nucleated by active HSP90, we characterized the network of functionally-related metabolic enzymes from the cytosol of DLBCL cells into metabosomes. Similar to other chaperone-containing phase-separated granules [18,44,45], it is possible that the transient, enzyme-enzyme interactions during catalysis become more stable in the context of HSP90-containing epichaperomes [26,27].…”

“…In a group of cancer subtypes that include DLBCL and BL, HSP90 organizes into higher order heterogeneous chaperome complexes termed epichaperomes that are more stable than the classical chaperomes characteristic of normal cells [27]. Contrary to classical transient chaperomes, whose function is to fold and stabilize proteins, the more permanent epichaperome complexes allow the maintenance of diverse macrocomplexes in active configurations [26,27]. We report here the discovery of a novel mechanism of metabolic regulation in cancer cells that is characterized by the HSP90dependent nucleation of enzymatic macrocomplexes.…”

“…The chaperome, an assembly of molecular stress chaperones and their many partners, assist in protein folding and in reducing protein aggregation to maintain cellular proteostasis. In cancer cells the heat shock protein 90 (HSP90) chaperome can be incorporated with the heat shock protein 70 (HSP70) chaperome to assemble higher-order structures regarded as "epichaperomes" [26]. Epichaperomes can increase, not just balancing, the fitness of the proteome in cancer cells by assisting in the formation of multi-protein complexes [26,27].…”

“…In cancer cells the heat shock protein 90 (HSP90) chaperome can be incorporated with the heat shock protein 70 (HSP70) chaperome to assemble higher-order structures regarded as "epichaperomes" [26]. Epichaperomes can increase, not just balancing, the fitness of the proteome in cancer cells by assisting in the formation of multi-protein complexes [26,27]. This function becomes critical for cancer proliferation on a background of internal and external stress that results from biological instability and changing microenvironmental conditions [6].…”