Muhammad Afzal

ASK1 Signaling in Cancer: Pathogenic Driver or Therapeutic Target?

ABSTRACT Apoptosis signal‐regulating kinase 1 (ASK1), an important member of the MAP kinase kinase kinase (MAP3K), has been identified as a significant modulator of cellular responses to oxidative stress, inflammatory responses, and endoplasmic reticulum stress. Structurally characterized by its thioredoxin‐binding domain, its kinase domain, and coiled‐coil structures, ASK1 relays downstream stimulation of JNK and p38 MAPK cascades. Yet, its role in cancer function is paradoxical and simultaneously serves as both a cancer inhibitor and an activator rely on cellular settings. In this article, an overview of the molecular biology of ASK1 is presented with emphasis on the elusive balance between stimulation and suppression by upstream molecules such as Trx, TRAF proteins, and ubiquitination machinery. We provide an overview of the dualistic role of ASK1 in cancer pathophysiology showing how its dysregulation leads to tumor development, metastasis, chemoresistance, or tumor suppression by pro‐apoptotic signals, respectively. An example of context‐dependent action is provided using the examples of different cancers including lung, breast, ovarian, and hepatocellular carcinoma. Moreover, we discuss new therapeutic approaches to ASK1 such as small‐molecule inhibitors, RNA therapies, and protein‐protein interaction modulation and speculate on their potential in personalized medicine. The article also deals with future opportunities in the sense of the bivalent character of ASK1 in developing context‐dependent and targeted cancer therapies. The key to unlocking the potential of ASK1 to be used as a therapeutic intervention and overcome the complications that are posed by its dualistic nature in cancer biology lie in the understanding of the complex regulatory network it forms.