Introduction

Over the past few years, the scientific community has been heavily invested in the exploration of diverse forms of regulated cell death (RCD), as they can offer new angles in the treatment of diseases, including cancer. Among these forms, ferroptosis—a regulated form of cell death caused by an overload of iron-dependent lipid peroxidation—has sparked immense interest. A recent study published in “Cancers,” highlights the role of TMEM16F/Anoctamin 6 (ANO6) in ferroptosis and the prospects it opens up in cancer therapy.

This article delves into the research exploring TMEM16F’s functionality, its involvement in ferroptotic cell death, and how this understanding can translate into novel interventions for cancer treatment. Additionally, the implications for not only cancer but also other diseases and physiology will be discussed.

DOI: 10.3390/cancers11050625

The study published in Cancers (Basel) by Ousingsawat, Schreiber, and Kunzelmann (2019) titled “TMEM16F/Anoctamin 6 in Ferroptotic Cell Death,” analyzes ANO6 as a key factor in the execution of ferroptosis. Their findings not only unravel the mysteries of ferroptotic cell death mechanisms but also raise the potential of ANO6 as a target in cancer therapies.

The TMEM16F Protein and its Functions

TMEM16F, also known as Anoctamin 6 (ANO6), is a member of the TMEM16/anoctamin family, which comprises ten proteins. These proteins are known for their crucial roles in a variety of cellular processes, including ion transport, phospholipid scrambling, and ultimately, the regulation of cell death (Ousingsawat et al., 2019).

ANO6 specifically has been identified as a key player in calcium (Ca2+)-dependent phospholipid scrambling—a process vital for proper cell membrane composition and function. Defects in ANO6 have been linked to Scott syndrome, a rare bleeding disorder, underlining the importance of ANO6 in coagulation and cell membrane repair (Suzuki et al., 2010).

Ferroptosis and ANO6

Ferroptosis is distinguishable from other types of cell death, such as necrosis and apoptosis, by its unique dependence on iron and reactive oxygen species (ROS). Stockwell et al. (2017) define ferroptosis as a form of programmed cell death characterized by the accumulation of lipid peroxides to lethal levels. This process is tightly regulated, and disruptions in cellular balance can trigger ferroptosis, leading to diseases or becoming a tool for therapeutics.

ANO6 has been identified as a facilitator of ferroptosis through its activity as a Ca2+-activated non-selective ion channel and a phospholipid scramblase. The overactivation of ANO6 leads to disruptions in cellular ion homeostasis and promotes the externalizing of phosphatidylserine (PS), a “eat-me” signal for macrophages, marking the cell for phagocytosis (Yang et al., 2012).

Implications in Cancer and Other Diseases

The study suggests that ANO6 activation contributes to ferroptosis by releasing Ca2+ into the cell, leading to oxidative stress and cell death, which can be harnessed against cancer cells (Ousingsawat et al., 2019). Additionally, ANO6’s expression in cancer appears to play a dual role; while in some contexts it might facilitate cancer progression, in others, it may act as a tumor suppressor (Kunzelmann et al., 2019).

The manipulation of ANO6’s activity and its signaling pathways could either promote or inhibit cancer growth, making it a compelling target for drug development. Inhibiting ANO6 could, in theory, suppress tumor growth by sabotaging the cell’s ability to cope with stress, while in certain cancers, inducing ferroptosis through ANO6 could be therapeutically beneficial (Wang et al., 2017).

In addition to cancer, ANO6 has broader physiological implications. It has been associated with diseases like cystic fibrosis and Scott syndrome. Therapeutic strategies aimed at correcting its function could have broader implications for diseases where phospholipid scrambling and ion transport play a significant role in pathology (Shimizu et al., 2013).

Moreover, ANO6 is involved in macrophage function and innate immunity (Ousingsawat et al., 2015), making it a multifaceted protein of interest beyond oncology.

Drug Development and Side Effect Management

As research progresses, the potential of manipulating ANO6 for therapeutic purposes becomes more tangible. Drugs targeting ANO6 must be developed with precision, balancing the benefits of inducing ferroptosis in cancer cells against the risks of harming normal cells.

Niclosamide, an anthelmintic drug, has been repurposed and shown to inhibit ANO6, providing an example of how existing drugs can be adapted to target new pathways in cancer therapy (Benedetto et al., 2019; Miner et al., 2019).

The Future of ANO6 in Cancer Treatment

Current cancer treatments often involve chemotherapy, radiation, and surgery. These methods can be invasive and come with significant side effects. Targeting the ferroptosis pathway through ANO6 offers an alternative strategy by using the body’s innate cell death mechanisms to eliminate cancer cells.

However, it is essential to consider the molecular heterogeneity among different types of cancers. ANO6’s role may vary significantly depending on the cancer subtype and the molecular landscape of individual tumors. Personalized medicine approaches will be necessary for the effective clinical application of ANO6-targeting drugs.

Conclusion

The potent role of ANO6 in ferroptosis provides a promising avenue for cancer treatment strategies. By understanding and manipulating this pathway, it may be possible to induce controlled cell death in cancer cells, offering hope for more targeted and less invasive therapies.

As of May 2019, the implications of this work are vast and offer fertile ground for further research, not only in the realm of oncology but also in understanding and treating other diseases that involve ANO6.

References

1. Ousingsawat J., et al. (2019). TMEM16F/Anoctamin 6 in Ferroptotic Cell Death. Cancers (Basel), 11(5): 625. doi: 10.3390/cancers11050625
2. Stockwell B.R., et al. (2017). Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171(2): 273–285. doi: 10.1016/j.cell.2017.09.021
3. Yang H., et al. (2012). TMEM16F Forms a Ca2+-Activated Cation Channel Required for Lipid Scrambling in Platelets during Blood Coagulation. Cell, 151(1): 111–122. doi: 10.1016/j.cell.2012.07.036
4. Wang H., et al. (2017). Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. Mol. Cancer, 16: 152. doi: 10.1186/s12943-017-0720-x
5. Benedetto R., et al. (2019). Niclosamide repurposed for the treatment of inflammatory airway disease. JCI Insight. Under Review. PMC6693830

Keywords

1. TMEM16F
2. ANO6
3. Ferroptosis
4. Cancer treatment
5. Calcium signaling
6. Lipid peroxidation
7. Programmed cell death
8. Regulated cell death