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Editorials
aka PDI), encoding the archetype PDI protein, and other members of the family are upregulated in many human tumors, correlate with invasiveness (metastasis) and, in some cases, may confer therapy resistance.8,9 These find- ings, along with the fact that the interplay between the ER and mitochondria is critical for survival versus death, motivated the authors and many other investigators to examine the role of PDI inhibitors in cancer treatment.
PS89 is a derivative of a lead compound discovered by the authors using a screen for chemosensitization of etoposide-induced apoptosis in a variety of cell lines.10 This initial work showed that PS89 is a reversible inhibitor of PDI and induced the UPR. However, in the current investigation, genetic silencing of PDI failed to recapitulate PS89 activity seen in leukemia cell lines and overexpression did not rescue the chemosensitizing effect. This launched the search for additional targets. It should be noted however that these experiments do not rule out an impact of the UPR in mediating PS89’s effect or its modulation of other PDI family members. Indeed, activity-based protein profiling performed by these inves- tigators did show that other PDI family proteins are tar- gets of PS89 as are other resident ER proteins.
B-cell receptor-associated protein 31 (BAP31) was one of the most prominent proteins identified as a PS89 bind- ing partner and is known to operate at the MAM. BAP31 is located at the ER membrane and is tethered to mito- chondria through mitochondrial fission protein 1 (FIS1), which appears to serve as a platform for procaspase 8. Previous work has shown that apoptotic signals originat- ing from the mitochondria lead to cleavage of BAP31 into the pro-death p20BAP31 fragment, thereby activating caspase 8 and launching/amplifying apoptosis.11 Kozcian and colleagues showed that etoposide or PS89 alone had only a modest impact on activation of caspase 8 and other downstream effector pathways, but the combination was highly effective at inducing activity. Moreover, they showed that the combination triggered increased ER- associated calcium influx, loss of mitochondria mem- brane integrity, cytochrome C release, and increased lev- els of reactive oxygen species. Other studies have shown that BAP31 plays a critical role in mediating ER stress- related apoptosis through interaction with cell death inducing p53 target 1 (CDIP) resulting in sequestration of BCL-2 and activation of BAX and caspase 8.12 Thus, BAP31 emerges as a hub for integrating a variety of apop- totic signals from both organelles. Furthermore, their work supports continued efforts to target this intercon- nected network with the aim of amplifying apoptotic sig- nals.
The authors emphasize the concept of “network phar- macology” in developing potential strategies for the development of novel cancer therapeutics. Given the myriad roles of PDI family members in cell homeostasis, inhibitors of these enzymes are likely to operate through multiple targets in orchestrating their impact in a variety of model systems. For example, two members of the fam- ily have opposing effects on the activation of PERK which, as mentioned, plays a key role in the UPR.13 PERK
inhibitors have been associated with unacceptable side effects and PDI inhibitors might provide an alternative, less toxic way to inhibit the ER’s ability to maintain homeostasis under stress. Likewise, a recent paper also published in Hematologica described that a thioredoxin inhibitor, SK053, promoted differentiation and apoptosis in acute myeloid leukemia cells.14 As in the experiments by Koczian et al., knock down of the target failed to repli- cate the phenotype also motivating the authors to search for other targets. In fact, they showed that SK053 binds to and inhibits PDI (i.e., the product of the PDIA1 gene). Previous work had shown that PDI interacts with a stem loop structure of the CCAAT enhancer-binding protein α (C/EBPα) and blocks its translation. Expression of C/EBPα is critical for myeloid differentiation and its activity is often corrupted in acute myeloid leukemia. PDI inhibi- tion overcomes the translational block leading to increased C/EBPα levels, differentiation and apoptosis in acute myeloid leukemia.
Thus, the observations by Koczian and others highlight the potential utility of targeting the MAM, a dynamic scaffold that plays a critical role in a variety of biological processes, using PDI inhibition or other approaches to augment a variety of cancer therapies.
References
1 Koczian F, Naglo O, Vomacka J, et al. Targeting the endoplasmic reticulum-mitochondria interface sensitizes leukemia cells to cytosta- tics. Haematologica. 2019;104(3):546-555.
2. Marchi S, Patergnani S, Pinton P. The endoplasmic reticulum-mito- chondria connection: one touch, multiple functions. Biochim Biophys Acta. 2014;1837(4):461-469.
3. Herrera-Cruz MS, Simmen T. Cancer: untethering mitochondria from the endoplasmic reticulum? Front Oncol. 2017;7(105).
4. Prudent J, McBride HM. The mitochondria-endoplasmic reticulum contact sites: a signalling platform for cell death. Curr Opin Cell Biol. 2017;47:52-63.
5. Kerkhofs M, Bittremieux M, Morciano G, et al. Emerging molecular mechanisms in chemotherapy: Ca(2+) signaling at the mitochondria- associated endoplasmic reticulum membranes. Cell Death Dis. 2018;9(3):334.
6. Giorgi C, Bonora M, Missiroli S, et al. Alterations in mitochondrial and endoplasmic reticulum signaling by p53 mutants. Front Oncol. 2016;6:42.
7. van Vliet AR, Agostinis P. Mitochondria-associated membranes and ER stress. Curr Top Microbiol Immunol. 2018;414:73-102.
8. Lee E, Lee DH. Emerging roles of protein disulfide isomerase in can- cer. BMB Rep. 2017;50(8):401-410.
9. Xu S, Sankar S, Neamati N. Protein disulfide isomerase: a promising target for cancer therapy. Drug Discov Today. 2014;19(3):222-240.
10. Eirich J, Braig S, Schyschka L, et al. A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells. Angew Chem Int Ed Engl. 2014;53(47):12960-12965.
11. Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S. Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J. 2011;30(3):556-568.
12. Namba T, Tian F, Chu K, et al. CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress. Cell Rep. 2013;5(2):331-339.
13. Kranz P, Neumann F, Wolf A, et al. PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR). Cell Death Dis. 2017;8(8):e2986.
14. Chlebowska-Tuz J, Sokolowska O, Gaj P, et al. Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells. Haematologica. 2018;103(11):1843-1852.
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