The Unfolded Protein Response in Glioblastomas: Targetable Or Trouble?

Abstract

Glioblastomas are devastating central nervous system tumors with abysmal prognoses. These tumors are often difficult to resect surgically, are highly invasive and proliferative, and are resistant to virtually all therapeutic attempts, making them universally lethal diseases. One key enabling feature of their tumor biology is the engagement of the unfolded protein response (UPR), a stress response originating in the endoplasmic reticulum (ER) designed to handle the pathologies of aggregating malfolded proteins in that organelle. Glioblastomas and other tumors have co-opted this stress response to allow their continued uncontrolled growth by enhanced protein production (maintained by chaperone-assisted protein folding) and lipid biosynthesis driven downstream of the UPR. These features can account for the extensive extracellular remodeling/invasiveness/angiogenesis and proliferative capacity, and ultimately result in tumor phenotypes of chemo- and radio-resistance. The UPR in general, and its chaperoning capacity in particular, are thus putative high-value targets for treatment intervention. Such therapeutic strategies, and potential problems with them, will be discussed and analyzed.

Proteomic analyses of brain tumor cell lines amidst the unfolded protein response

“…These results indicate successful UPR induction in the UPN933 cells. We should note that the upregulation of CHOP/GADD153 is not necessarily a harbinger of apoptosis, as expression levels were quite variable in our previous study [15], and its subcellular localization (eg, cytosolic vs nuclear) may play a role in its biologic activity [11]. …”

“…The UPR plays roles in human tumors affecting different aspects of tumorigenesis [32]. However, little is known about the UPR in brain tumor biology [11, 16, 33], particularly the molecular identities involved in downstream processes. We employed mass spectrometry techniques analyzing the global proteomes of two high grade glioma lines under homeostatic and stress conditions.…”

“…If this accumulation of unfolded proteins occurs in the endoplasmic reticulum (ER), it will lead to ER stress, which may activate the unfolded protein response (UPR). Activation of the UPR leads to an increase in the protein folding capacity of the ER by chaperone protein upregulation, an overall reduction in global protein translation (thus decreasing overall protein input), and an increase in degradation of misfolded proteins until homeostatic conditions are restored, or the cell commits to apoptosis [10, 11]. In response to the activation of the UPR, three arms of the UPR transduction pathways modulate transcriptional and translational changes necessary to return the cell to homeostatic conditions, or to instigate apoptosis [10].…”

“…These cellular stressors lead to the activation of the UPR and have been shown to play roles in different aspects of tumor development and progression [14]. Our lab previously showed that activation of UPR results in increased metabolism and chemo-resistance in xenograft tumors and parent cell lines [15]; however, little else is known about the role of the UPR in brain tumors [11, 16]. …”

Protein Misfolding Diseases

“…Martin L Duennwald illustrates how cooperation between these different stress response pathways might play an important role in defining protein toxicity in Huntington's and other brain disorders [8]. In fact, the devastating CNS glioblastomas exploits the unfolded protein response to allow their continued uncontrolled growth, becoming thus a potential target for treatment intervention, as reviewed by Michael Graner [9]. Spinal and bulbar muscular atrophy, is a neuromuscular degenerative disease that, as in the case of the better characterized Huntignton's disease, arises from expansion of the polyglutamine repeats, in this case in the androgen receptor, indicating that similar sequential changes might lead to different disorders depending on the protein target in which they occur, as reported by Folake A Orafidiya and Iain J McEwan [10].…”