In an important proof-of-concept study, scientists have successfully employed a ferroptosis activator and an mTOR inhibitor against bladder cancer cells [1].
Ferroptosis – “the iron death”
Ferroptosis is a distinct type of cell death that gets less attention and is less well understood than the more ubiquitous and familiar apoptosis. As its name suggests, ferroptosis requires iron to activate complex pathways that eventually lead to the cell’s demise. Since cancer cells generate higher levels of iron, they are more susceptible to ferroptosis, which is why it has been receiving a lot of recent attention from oncologists. Some ferroptosis inducers have already been tested against cancer in early research, even if scientists may not know the exact mechanisms of their action yet. Ferroptosis also definitely plays a role in aging (again, not fully elucidated) – for instance, one recent study found a significant age-dependent increase in ferroptosis in numerous tissues in mice [2].
Autophagy and cancer – a complex relationship
It is becoming increasingly evident that ferroptosis, at least sometimes, uses autophagy pathways. Autophagy is the process of recycling cellular garbage such as misfolded proteins, and it has a complex, context-dependent relationship with cancer. Autophagy is thought to have a protective function during tumorigenesis, but once tumor cells are established, autophagy supports tumor survival and metastasis. Several previous studies showed the contrasting effects of autophagy in bladder cancer [3].
Autophagy can be employed against cancer, such as via inhibitors of the nutrient sensing complex mTOR, of which rapamycin is the most famous. The logic behind this particular facet of autophagy-cancer interplay goes like this: cancer cells require a lot of energy for growth and their unstoppable proliferation. mTOR inhibition, on the other hand, tricks cells into thinking that nutrients are in short supply. This slows down cellular metabolism and activates autophagy so that cells obtain nutrients by recycling those leftover molecules. Neglected when life is good and nutrients are abundant, autophagy results in slower proliferation but also in cleaner and leaner cells. Upregulating autophagy is probably one of the mechanisms behind rapamycin’s geroprotective action [4].
How can autophagy be involved in cell death if it is supposed to make cells younger and healthier? This is probably because biology creatively uses whatever is at hand, so many biological processes have multiple, sometimes mutually exclusive, purposes. Depending on the context, autophagy can accompany cell death, be a part of a signaling pathway that leads to cell death, or even directly cause it [5].
Twin power
In their study, the researchers first experimented with the ferroptosis inducer Fin56. In a series of experiments, they confirmed that Fin56 induced death in many, but not all, bladder cancer cells; that this cellular death was ferroptosis; and that this ferroptosis was autophagy-dependent in at least two lines of bladder cancer cells. Autophagy inhibition, as expected, greatly reduced Fin56-mediated ferroptosis. According to the researchers, not only does ferroptosis correlate with autophagy, it actively uses autophagy mechanisms to kill cells.
Torin 2, an mTOR inhibitor, was added to the equation. After 72 hours of treating two bladder cancer cell lines with the Torin 2 – Fin56 duo, only a tiny fraction of the cells remained viable. Yet, the results were heavily dependent on dosage: this almost complete eradication of the cancer cells was achieved only at the highest concentrations of Torin 2. The safe dosage in living organisms, including humans, remains to be seen. What is clear, though, is that these two autophagy-related processes running simultaneously greatly amplify the overall effect, which can potentially be used in cancer therapies.
Conclusion
Bladder cancer is the 10th most common cancer worldwide, responsible for an estimated 549,000 new cases and 200,000 deaths per year. As recent research shows, current methods of choice in cancer therapy, including chemotherapy, radiotherapy, are harmful and also seem to accelerate aging in survivors [6]. This makes finding new, less toxic methods a necessity. The interplay between autophagy and cancer is intriguing and complex, given that both its promotion and inhibition seem to have anti-cancer effects, sometimes in the same cancer type. This new research expands our understanding of the subject by showing how autophagy can be synergistically amplified by a duo of molecules to effectively quash bladder cancer cells.
Literature
[1] Sun, Y., Berleth, N., Wu, W., Schlütermann, D., Deitersen, J., Stuhldreier, F., … & Stork, B. (2021). Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death & Disease, 12(11), 1-14.
[2] Zheng, H., Jiang, L., Tsuduki, T., Conrad, M., & Toyokuni, S. (2021). Embryonal erythropoiesis and aging exploit ferroptosis. Redox Biology, 102175.
[3] Li, F., Guo, H., Yang, Y., Feng, M., Liu, B., Ren, X., & Zhou, H. (2019). Autophagy modulation in bladder cancer development and treatment. Oncology reports, 42(5), 1647-1655.
[4] Sarkar, S., Ravikumar, B., Floto, R. A., & Rubinsztein, D. C. (2009). Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death & Differentiation, 16(1), 46-56.
[5] Denton, D., & Kumar, S. (2019). Autophagy-dependent cell death. Cell Death & Differentiation, 26(4), 605-616.
[6] Wang, S., Prizment, A., Thyagarajan, B., & Blaes, A. (2021). Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment. Cancers, 13(3), 427.
