Introduction: Abstract
Introduction
Cancers have always been very challenging to beat. Defeating cancer and tumor progression is a big objective and also a great concern in biomedicine area. various means are widely known to defeat cancer and inhibit tumor progression like chemotherapy and radiation. But in cellular and molecular scales, everything is a bit different. Nonetheless, tumors are excessively proliferating cells; therefore, stopping them through inhibition of internal and molecular factors is a better way to remove them from the body. Among cellular and molecular pathways and factors, necroptosis is a promising but controversial way to delete cancerous cells.
Methods: As it may be known, necroptosis is a regulated and programmed inflammatory-mediated necrotic cell death, which is different from autophagy and apoptosis. Necroptosis is an immune cellular response based pathway which can be considered as an immunogenic necrosis for tumor cells. It can be effective in all stages of cancer, including oncogenesis or cancer intiation, tumor progression and also metastasis. Activation and even modification of molecular mechanisms of necroptosis for modulation of different stages of cancer is being discussed to take advantage of this promising and effective way of cell death.
Results: One of the main components of necroptosis are Receptor Interaction Protein Kinases (RIPK), especially type 1 and 3, which play an important role in the mechanism of necroptosis. Activation of these RIPKs can be triggered by various stimuli and subsequently regulate necroptotic pathway in the target cells. Another main component of this pathway is Mixed Lineage Kinase Domain-Like Protein (aka MLKL) which is a substrate to RIPK3. understanding the pathway details is highly essential in order to use this tool in anticancer therapy, although precise pattern of its mechanism is still to be discovered.
Conclusion: With current knowledge, the main mechanism is Caspase independent and generally based on the interaction between RIPK 1 and 3 and MLKL protein. Multiple stimuli can elicit necroptotic pathway including cytokines and Damage-Associated Molecular Patterns (DAMPs), which can evoke inflammatory and immune responses to induce cell death. Cytokines that can trigger necroptosis include Tumor Necrosis Factors (TNFs) and Interferon (IFN) family. The process of necroptosis should initiate with one of the stimuli such as TNF-α, resulting in activation of TNF Receptor, activation RIPK1 and RIPK3 , phosphorylation and oligomerization of MLKL leading to necrosome formation to disrupt membrane integrity and release microchemicals. necroptosis is also an effective strategy when the cancerous cells are resistant to apoptosis; due to inactivation, inhibition or alteration of caspase activity in them. Hereby, induction of necroptosis would be a solution of omission of these tumor cells. But in general, some of the necroptosis characteristics can cause the dual function of this pathway, making it a so-called two-edged sword in cancer therapy. It can either suppressive or promotive to the tumor cells under certain conditions and circumstances. Targeting the key components and steps of this process can modify the exact function, which is tumor suppression and cancer cells eradication.