Abstract
Endoplasmic reticulum glycoprotein folding quality control (ERQC) and ER-associated degradation (ERAD) preside over cellular glycoprotein secretion and maintain steady glycoproteostasis. When cells turn malignant, cancer cell plasticity is affected and supported either by point mutations, preferential isoform selection, altered expression levels, or shifts to conformational equilibria of a secreted glycoprotein. Such changes are crucial in mediating altered extracellular signalling, metabolic behavior, and adhesion properties of cancer cells. It is therefore conceivable that interference with ERQC and/or ERAD can be used to selectively damage cancers. Indeed, inhibitors of the late stages of ERAD are already in the clinic against cancers such as multiple myeloma. Here, we review recent advances in our understanding of the complex relationship between glycoproteostasis and cancer biology and discuss the potential of ERQC and ERAD modulators for the selective targeting of cancer cell plasticity.
Highlights
Plasticity, an intrinsic characteristic of healthy cells in biological contexts as varied as embryonal development [1], tissue development and repair [2], adaptation to injury [3], and wound healing [4], is central to cancer initiation, progression, and metastasis. e proteins establishing and maintaining cancer plasticity are good anticancer drug targets in the fight against cancer initiation, progression, and therapy resistance itself [5]
A large number of published studies have highlighted the dependency of a number of cancers on specific endoplasmic reticulum glycoprotein folding quality control (ERQC)/ endoplasmic reticulum associated degradation (ERAD) components, but the lack of specific inhibitors of the components in both pathways has hampered proper characterisation of the roles played by ERQC/ERAD in cancer biology
Even if such specific inhibitors were available, in order to make a convincing case for ERQC/ERAD as valid anticancer targets, several aspects of ERQC/ERAD biology in healthy and cancer cells need to be better elucidated
Summary
Plasticity, an intrinsic characteristic of healthy cells in biological contexts as varied as embryonal development [1], tissue development and repair [2], adaptation to injury [3], and wound healing [4], is central to cancer initiation, progression, and metastasis. e proteins establishing and maintaining cancer plasticity are good anticancer drug targets in the fight against cancer initiation, progression, and therapy resistance itself [5]. E proteins establishing and maintaining cancer plasticity are good anticancer drug targets in the fight against cancer initiation, progression, and therapy resistance itself [5]. E therapeutic value of pharmacological chaperones (small molecules stabilising a misfolded glycoprotein as it traverses the ER) is already well established in a number of congenital glycoprotein misfolding endocrine and metabolic disorders [12], further supporting the idea that therapeutic modulation of ER glycoprotein folding and degradation systems could be successfully applied to cancer treatment, at least in cases where ERQC-assisted glycoprotein folding and ERAD play a major role. Given the unique and central role of ERQC/ERAD in the fate of hundreds of secreted glycoproteins, and remembering that plasticity of different cancers depends on different subsets of secreted glycoproteins, ERQC/ERAD modulating drugs may have the potential to represent broad-spectrum anti-cancer agents. We review our current understanding of how ERQC/ERAD preserve ER glycoproteostasis and discuss how we may harness the molecular detail so far established on these systems in order to develop new broad-spectrum anti-cancer therapeutics
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