Golgi Apparatus and Cancer: Targeting Enzymes and Pathways for Novel Therapeutic Approaches

Targeting Golgi-Related Enzymes in Cancer Therapy

One of the strategies used in the identification of the Golgi apparatus in cancer treatment is by bombardment of particular enzymes in essential pathways. For example, Golgi mannosidase II (GMII), an enzyme that is involved in the processing of N-glycans, which are involved in cell-cell interactions and signaling. There are stern efforts to design small molecules targeting GMII because of their potent anticancer properties due to their capability of inhibiting glycosylation changes that are pervasive in cancer cells. Nonetheless, the synthesis of selective GMII inhibitors remained a problem since its potent analogs elicited adverse effects linked to inherited lysosomal storage diseases. New approaches have been made in recent years that brought forward new inhibitors that have different binding profiles more suitable for targeting solely GMII with an increased likelihood of success at treating cancer.

Another enzyme is cyclooxygenase-2 (COX-2), which, as well as being overexpressed in numerous tumors, has been associated with inflammation and cancer proliferation. Bodipy-based COX-2 selective fluorescent probes have been designed for targeting the Golgi apparatus that permits visualizing Golgi-related events in cancer cells. These probes facilitate the determination of cancer cells and the dynamic changes of the Golgi apparatus during cancer development, providing potential for diagnosis and treatment.

Golgi Fragmentation and Its Impact on Cancer Cell Behavior

Golgi fragmentation is a well-documented occurrence in different types of cancer, such as breast, lung, and prostate cancer. These changes in Golgi’s ultrastructure are not a simple reaction to cellular stress but rather an influence on cancer cell movement and metastasis. Disassembly of the Golgi helps direct protein and vesicles to the front of the moving cells, which supports cancer cell migration. Specifically, it was observed that IGF-1R, an important signaling receptor, localizes to the direct apparatus in response to phosphorylation signals, which promote cancer cell movement. It could affect the enzymes and processes that control these phenomena and thereby weaken the ‘assaultiveness’ of carcinogenic cells.

Cyclin-dependent kinase 5 (CDK5) is involved in dEGFR and Golgi fragmentation in Alzheimer’s disease, while this mechanism is identical to that in cancer. It was observed that interference with the CDK5 activity helps to revert Golgi disorganization and decrease cancer cells’ ability to migrate and invade, thus it could be a potential therapeutic target in cancer. Hence, through the regulation of phosphorylation of specific Golgi proteins, including GRASP65, it is possible to orchestrate the structural and functional integrity of the Golgi in cancer cells or any other pathologic context that may distort its normal localization and function and evoke pro-migratory signals.

Golgi-Targeted Drug Delivery Systems

The fact that targeted drug delivery systems that make use of the properties of the Golgi apparatus is an encouraging therapeutic prospect. One of the potential methods is based on crescent microgels with antibodies immobilized on their surfaces and enzymes such as glucose oxidase. These microgels exploit and destroy cancer cells by mounting a high concentration of reactive oxygen species inside the Golgi system with a minimal effect on the surrounding healthy cells. This method demonstrates the goals set by applying the Golgi apparatus as a specific site to direct anti-cancer drugs, thus avoiding unwanted general side effects of chemotherapy.

Other strategies are supramolecular nanomedicines ready to inflict two anticancer drugs on the tumor’s Golgi apparatus. These nanomedicines work as “Trojan horses”: They carry drugs across cell membranes and facilitate their accumulation in the Golgi apparatus Just where their healing properties become apparent. These delivery systems can accumulate drugs within the Golgi, where they can abolish the function of cancer cell processes that are dependent on healthy Golgi function, such as glycosylation and protein trafficking, making them a potent weapon against cancer.

Future Directions and Therapeutic Potential

The targeting of the Golgi apparatus and its associated enzymes presents a novel and underexplored avenue for cancer therapy. As our understanding of the Golgi’s role in cancer continues to evolve, new therapeutic targets and strategies are likely to emerge. Future research should focus on the identification of additional Golgi-specific enzymes and pathways that can be modulated to inhibit cancer progression. Furthermore, the development of selective inhibitors and targeted delivery systems that minimize off-target effects will be crucial for translating these findings into clinical practice.

A significant challenge lies in understanding the full extent of Golgi-related disruptions in cancer and how they can be leveraged therapeutically. The integration of advanced imaging techniques and molecular biology tools will aid in elucidating the complex interactions between the Golgi and cancer cell signaling networks. Ultimately, the ability to specifically target the Golgi apparatus could revolutionize cancer treatment, offering more precise and effective therapies with reduced side effects.

Conclusion

The Golgi apparatus has been shown to have several functions in cancer, including cell motility, invasion, and overall tumor development. Through delighting in Golgi-associated enzymes and pathways, investigators are identifying several new prospects that could dramatically affect tumor therapy. From the inhibitors of enzymes to the pharmaceutics targeted delivery systems, the Golgi apparatus is becoming a major target in cancer research. Future studies in this area will help establish unique methods to inhibit the functionality of cancer-producing cells and enhance the prognosis of patients suffering from the disease.

References

1. Hu, X., Hai, Z., Wu, C., Zhan, W. and Liang, G., 2020. A golgi-targeting and dual-color “turn-on” probe for spatially precise imaging of furin. Analytical Chemistry, 93(3), pp.1636-1642.
2. He, H., Tan, W., Guo, J., Yi, M., Shy, A.N. and Xu, B., 2020. Enzymatic noncovalent synthesis. Chemical reviews, 120(18), pp.9994-10078.
3. Armstrong, Z., Kuo, C.L., Lahav, D., Liu, B., Johnson, R., Beenakker, T.J., De Boer, C., Wong, C.S., Van Rijssel, E.R., Debets, M.F. and Florea, B.I., 2020. Manno-epi-cyclophellitols enable activity-based protein profiling of human α-mannosidases and discovery of new Golgi mannosidase II inhibitors. Journal of the American Chemical Society, 142(30), pp.13021-13029.
4. He, H., Liu, S., Wu, D. and Xu, B., 2020. Enzymatically formed peptide assemblies sequestrate proteins and relocate inhibitors to selectively kill cancer cells. Angewandte Chemie, 132(38), pp.16587-16592.
5. Rieger, L., O’Shea, S., Godsmark, G., Stanicka, J., Kelly, G. and O’Connor, R., 2020. IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251. Science Signaling, 13(633), p.eaba3176.
6. Liu, Q., Yuan, Z., Guo, X. and van Esch, J.H., 2020. Dual‐functionalized crescent microgels for selectively capturing and killing cancer cells. Angewandte Chemie International Edition, 59(33), pp.14076-14080.
7. Hatori, Y., Kubo, T., Sato, Y., Inouye, S., Akagi, R. and Seyama, T., 2020. Visualization of the redox status of cytosolic glutathione using the organelle-and cytoskeleton-targeted redox sensors. Antioxidants, 9(2), p.129.