Microtubules, crucial for cell division and structural integrity, play an essential role in the dynamics of cancer cells. Drugs like Taxol, used in chemotherapy, target these structures by stabilizing them to inhibit cell division. However, the discovery of UNC-45A, an ATP-independent microtubule-severing protein, introduces a new understanding of these dynamics.
Professor Martina Bazzaro and her team at the University of Minnesota, including Asumi Hoshino, Dr. Valentino Clemente, Mihir Shetty, Dr. Brian Castle, and Professor David Odde, have uncovered UNC-45A’s unique role in microtubule dynamics, opening up new avenues in cancer treatment research.
To explore the role of UNC-45A, the team employed a combination of in vitro biophysical reconstitution and total internal fluorescence microscopy analysis. They recreated cellular conditions in a controlled setting to observe how UNC-45A interacts with microtubules, focusing on its preference for binding to curved microtubules over straight ones. Additionally, they manipulated UNC-45A levels in cells to observe its impact on microtubule curvature.
Professor Bazzaro explains, “UNC-45A–mediated MT severing is preceded by the appearance of MT bends. While MTs are stiff biological polymers in cells, they often curve, and the result of this curving can be breaking off.” This insight highlights the unique mechanism by which UNC-45A influences microtubule behavior, a departure from the usual ATP-dependent severing proteins.
In a remarkable finding, the study reveals that UNC-45A induces curvature in microtubules even in the presence of Taxol. While Taxol is known to straighten microtubules, the team observed that Taxol-treated microtubules become less stiff and more wavy in vitro, yet straighten in cellular environments.
The implications of this discovery are profound for understanding cancer cell resistance to chemotherapy. Professor Bazzaro notes, “Despite this [straightening effect of Taxol], UNC-45A retains its ability to induce curvature in Paclitaxel-exposed MTs.” This suggests that UNC-45A might play a role in the development of chemoresistance in cancer cells, presenting new challenges and opportunities for therapeutic intervention.
The research is pivotal not only in oncology but also in understanding other conditions involving disrupted microtubule dynamics, such as neurodegenerative diseases. The unique ATP-independent mechanism of UNC-45A may offer an advantage in diseases characterized by reduced ATP levels and high oxidative stress.
In conclusion, the University of Minnesota’s research provides critical insights into UNC-45A’s role in microtubule dynamics and opens up new possibilities for treating diseases where microtubule stability is crucial. The findings pave the way for more effective and targeted therapies, enriching our understanding of cellular structures and their interactions with drugs.
Martina Bazzaro, Asumi Hoshino, Valentino Clemente, Mihir Shetty, Brian Castle, David Odde, “The microtubule-severing protein UNC-45A preferentially binds to curved microtubules and counteracts the microtubule-straightening effects of Taxol,” Journal of Biological Chemistry, 2023. DOI: https://doi.org/10.1016/j.jbc.2023.105355
About the Author
Dr. Bazzaro is a Tenured Associate Professor in the Department of Obstetrics, Gynecology and Women’s Health and Masonic Cancer Center at the University of Minnesota. She earned a Ph.D. in Medicinal Chemistry from the Department of Pharmaceutical Science of the University of Ferrara, Italy. Dr. Bazzaro served as guest researcher at the “Institut de Biochemie” in Lausanne, Switzerland and at the Karolinska Institute in Stockholm, Sweden. She completed her postdoctoral training at the Department of Pathology of the Johns Hopkins Hospital.
Dr. Bazzaro has a lifelong research interest in cervical and ovarian cancer. She combines her expertise in both the biology of ovarian cancer and pharmaceutical chemistry for the discovery of personalized medicine for women affected by cervical and ovarian cancer for which conventional chemotherapy is not a satisfactory option. Dr. Bazzaro’s laboratory is interested in studying abnormalities of protein degradation pathways in breast and ovarian cancer. The Ubiquitin-Proteasome-System (UPS) is responsible for degradation of over 90% of short-lived intracellular proteins. Protein degradation through Ubiquitin-Proteasome-System is a multistep process that begins with de-ubiquitination of ubiquitin-tagged target molecules by de-ubiquitinating enzymes following their entrance in the 20S catalytic chamber of the proteasomes were the actual degradation occurs. The polypeptide targets of the proteasome include proteins involved in cell cycle progression, survival and inflammation and while the ubiquitin-dependent proteasomal degradation is crucial for both normal and malignant cells the higher demand for metabolic/catabolic activity associated with the malignant phenotype renders the ubiquitin-proteasome pathway a suitable tool for cancer treatment. The laboratory is particularly interested in studying the role played by proteasomal- and lysosomal-assisted protein degradation pathways during the development and the progression of breast and ovarian cancer and in the development of new small-molecules inhibitors of ubiquitin-proteasome-system for targeting breast and ovarian cancer cells.