In a groundbreaking research article published in Cellular Physiology and Biochemistry, an eminent international journal of experimental cellular physiology, biochemistry, and pharmacology, scientists have delved into the complex interplay between gene expression regulation and cancer treatment. The study, entitled “RING1 Inhibition Has a Cell-Specific Antitumoral Role by Promoting Autophagy in Endometrial Cancer Cells,” opens new vistas in understanding how certain proteins implicated in histone modification affect autophagy—a fundamental process for cellular cleaning and recycling—in the fight against endometrial cancer.

DOI: 10.33594/000000679

The research conducted by Aleksandra A. Szustka, Karolina K. Kozal, and Anna A. Krześlak from the University of Lodz focuses on RING1A and RING1B proteins, key components involved in the enzymatic activity of the Polycomb repressive complex 1 (PRC1) that monoubiquitylates histone H2A. This biochemical modification plays a pivotal role in chromatin architecture and gene expression.

Autophagy, a survival mechanism of cells under stress, has been studied extensively for its role in cancer, both as a tumor suppressor and, paradoxically, as a means for tumor cells to endure nutrient shortage or treatment stress. The deregulation of autophagy is thus a double-edged sword: while it can contribute to cancer cell death when properly maneuvered, its mismanagement can also aid in the survival of malignancies.

Szustka et al.’s study pivots on this premise, with particular attention paid to endometrial cancer cells. Specifically, they investigated the effects of inhibiting RING1 proteins in endometrial cancer cell lines HEC-1A and Ishikawa, assessing whether this inhibition could induce autophagic responses conducive to cancer cell demise. The cells were treated with PRT4165, a known RING1 inhibitor, under varying glucose concentrations to simulate different metabolic states.

Their work provides compelling evidence that RING1 inhibition does indeed spur changes in the expression of autophagy-related (ATG) genes and proteins, suggesting that PRT4165 influences autophagic pathways. Yet, when coupled with known autophagy inhibitors, such as HCQ or Lys05, the anticancer efficacy of PRT4165 surprisingly diminished. This underscored that the intended autophagy-promoting anticancer strategy might not be as straightforward as previously imagined.

The study spotlights the nuanced nature of autophagy’s relationship with cancer cell survival and highlights the need for tailored approaches in leveraging autophagy modulation for therapeutic benefit. Even more intriguingly, the effects of RING1 inhibition on autophagy were found to vary not only with the glucose availability, a critical metabolic factor but also between different types of endometrial cancer cells, pointing to a highly cell-specific therapeutic impact.

The importance of this finding cannot be overstated, as it suggests a RING-centric avenue for cancer treatment that could vary from patient to patient or even cell to cell. While the researchers caution against the combination of PRT4165 with autophagy inhibitors as a viable anticancer strategy, they advocate for further exploration into more effective combinatorial approaches using autophagy modulators.

The study was funded by the National Science Centre Poland under grant UMO-2018/31/N/NZ5/01046.

References

1. Szustka Aleksandra A., Kozal Karolina K., Krześlak Anna A. (2024). RING1 Inhibition Has a Cell-Specific Antitumoral Role by Promoting Autophagy in Endometrial Cancer Cells. Cell Physiol Biochem, 58(1), 1-13. DOI: 10.33594/000000679

2. Kroemer, G., & Levine, B. (2008). Autophagic cell death: the story of a misnomer. Nature Reviews Molecular Cell Biology, 9(12), 1004-1010. DOI: 10.1038/nrm2529

3. White, E. (2012). The role for autophagy in cancer. Journal of Clinical Investigation, 122(1), 42-46. DOI: 10.1172/JCI62134

4. Green, D. R., & Levine, B. (2014). To die or not to die: how does autophagy decide? Cell, 157(1), 65-75. DOI: 10.1016/j.cell.2014.02.016

5. Towers, C. G., & Thorburn, A. (2016). Therapeutic targeting of autophagy. EBioMedicine, 14, 15-23. DOI: 10.1016/j.ebiom.2016.11.007

The study is crucial for furthering our understanding of how cellular processes like autophagy can be manipulated to target cancer cells selectively. It also demonstrates the necessity for personalized medicine approaches in the treatment of cancers, such as endometrial carcinoma, where cellular heterogeneity within the tumor microenvironment can significantly impact therapeutic outcomes.

Keywords

1. Autophagy
2. Endometrial Cancer Treatment
3. RING1 Inhibitor
4. PRT4165
5. Histone Modification

© Copyright by the Author(s). Published by Cell Physiol Biochem Press.

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Last Update: January 31, 2024