Dear Editor,

We read with keen interest the review article titled “Spatial Dynamics of TRAIL Death Receptors in Cancer Cells” that was published in Drug Resistance Updates.[1]

The authors clarified the intricate processes controlling the expression and activity of the TRAIL (TNF-related apoptosis-inducing ligand) receptors (DR4 and DR5), especially regarding the resistance of cancer cells to rhTRAIL. The elaborate experimental setup and in-depth data analysis described in this article contribute significantly to our knowledge of the posttranslational changes affecting the behavior of the TRAIL receptor and how they may affect treatment approaches. TRAIL is an essential player in the control of apoptosis. When it attaches itself to the death receptors DR4 and DR5, a signaling cascade that causes programmed cell death is started. This process holds particular significance in the field of cancer treatments, as it enables the targeted activation of apoptosis in cancer cells.[2] [3] In context with the continuous effort to create more potent cancer treatments, the authors' investigation of TRAIL and its receptors is a relevant and significant contribution to the area. It was very informative to read about the complex glycosylation mechanisms by which the authors altered TRAIL receptors. The article offers critical insights into how these alterations impact cellular sensitivity to TRAIL by describing the functions of certain glycosylation enzymes, such as GALNT14, and the consequences of O- and N-linked glycosylation on receptor stability and function. A substantial amount of knowledge on the regulation of these receptors is added by the discussion of the trafficking pathways of TRAIL receptors to the plasma membrane, including the functions of cargo transport proteins and nuclear localization signals. The authors' finding of endocytosis pathways further highlights the complex nature of receptor modulation and its influence on TRAIL-induced apoptosis, including both clathrin-dependent and -independent processes. Furthermore, the article's analysis of the interaction between oncogenic Ras pathways and TRAIL signaling is a noteworthy addition to the article. The authors successfully illustrate the relationship between H-Ras overexpression and TRAIL resistance in many cancer cell lines by using genome-wide mRNA expression data. This discovery is especially significant since it clarifies the effects of Ras proteins on TRAIL sensitivity that are isoform-specific and creates new opportunities for targeted treatments.[1]

The article is a great addition to the area, but there are a few more things to take into account that can increase its influence even more. It would be very beneficial to provide more precise future study paths and to broaden the conversation on the therapeutic significance of these results. For example, additional specific applications of the findings might be provided by describing possible combination treatments and providing details on how the modification of DR4 and DR5 surface expression can be incorporated into current cancer therapy regimens. It would also give a more defined path for clinical application, which would improve the study's translational component.[4] The article might also be strengthened by addressing the present shortcomings in immunohistochemistry for differentiating membrane-bound receptors from cytosolic fractions. It would deepen the conversation to suggest advanced diagnostic methods for precisely determining receptor location in clinical samples. Investigating these approaches might greatly enhance the process of determining which patient subgroups are most likely to benefit from treatments that target the TRAIL receptor.[5]

Furthermore, even if the in vitro results are strong, the case for clinical translation may be strengthened by adding more information or citations to in vivo model validation. In addition to strengthening the overall impact of the study, proving the effectiveness of possible combinational medicines in animal models would provide a more solid basis for upcoming clinical trials. Stressing how crucial multidisciplinary cooperation is to the advancement of this profession could also be helpful. Molecular biologists, clinical oncologists, and bioengineers may collaborate to create novel treatment approaches and diagnostic instruments, which would hasten the use of these discoveries in clinical settings.[6]

A solid basis for further investigation into TRAIL receptor-mediated apoptosis and cancer treatment has been established by the studies reported in this article. By implementing these recommendations, the article might provide an even more thorough and significant addition to the area. It is impressive that researchers were able to clarify the intricate regulation processes of TRAIL receptors, and their discoveries opened up a possible path for the creation of more potent cancer treatments. Finally, we would like to commend the authors for their careful study and important additions to our knowledge of the biology of the TRAIL receptor. Their research has made a substantial contribution to the area and provides information that may influence future treatment approaches. Also, the article will have even more of an effect and further establish its significance in the ongoing effort to overcome cancer resistance to targeted treatments by taking into account the other factors described above.

References

1. Twomey JD, Kim S-R, Zhao L, Bozza WP, Zhang B. Spatial dynamics of TRAIL death receptors in cancer cells. Drug Resist Updat 2015; 19: 13-21
   Crossref PubMed Search in Google Scholar
2. Guerrache A, Micheau O. TNF-related apoptosis-inducing ligand: non-apoptotic signalling. Cells 2024; 13 (06) 521
   Crossref PubMed Search in Google Scholar
3. Green DR. The death receptor pathway of apoptosis. Cold Spring Harb Perspect Biol 2022; 14 (02) a041053
   Crossref PubMed Search in Google Scholar
4. Gampa SC, Garimella SV, Pandrangi S. Nano-TRAIL: a promising path to cancer therapy. Cancer Drug Resist 2023; 6 (01) 78-102
   Crossref PubMed Search in Google Scholar
5. Hawes D, Shi SR, Dabbs DJ, Taylor CR, Cote RJ. Immunohistochemistry. In: Weidner N, Cote RJ, Suster S, Weiss LM. eds. Modern Surgical Pathology. 2nd ed. New York, NY:: Elsevier;; 2009: 48-70
   Search in Google Scholar
6. Witkowski J, Polak S, Pawelec D, Rogulski Z. In vitro/in vivo translation of synergistic combination of MDM2 and MEK inhibitors in melanoma using PBPK/PD modelling: part III. Int J Mol Sci 2023; 24 (03) 2239
   Crossref PubMed Search in Google Scholar

Address for correspondence

Publication History

Article published online:
17 January 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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References

1. Twomey JD, Kim S-R, Zhao L, Bozza WP, Zhang B. Spatial dynamics of TRAIL death receptors in cancer cells. Drug Resist Updat 2015; 19: 13-21
   Crossref PubMed Search in Google Scholar
2. Guerrache A, Micheau O. TNF-related apoptosis-inducing ligand: non-apoptotic signalling. Cells 2024; 13 (06) 521
   Crossref PubMed Search in Google Scholar
3. Green DR. The death receptor pathway of apoptosis. Cold Spring Harb Perspect Biol 2022; 14 (02) a041053
   Crossref PubMed Search in Google Scholar
4. Gampa SC, Garimella SV, Pandrangi S. Nano-TRAIL: a promising path to cancer therapy. Cancer Drug Resist 2023; 6 (01) 78-102
   Crossref PubMed Search in Google Scholar
5. Hawes D, Shi SR, Dabbs DJ, Taylor CR, Cote RJ. Immunohistochemistry. In: Weidner N, Cote RJ, Suster S, Weiss LM. eds. Modern Surgical Pathology. 2nd ed. New York, NY:: Elsevier;; 2009: 48-70
   Search in Google Scholar
6. Witkowski J, Polak S, Pawelec D, Rogulski Z. In vitro/in vivo translation of synergistic combination of MDM2 and MEK inhibitors in melanoma using PBPK/PD modelling: part III. Int J Mol Sci 2023; 24 (03) 2239
   Crossref PubMed Search in Google Scholar