Promising and challenging phytochemicals targeting LC3 mediated autophagy signaling in cancer therapy
Authors: Rajendran Peramaiyan , Renu Kaviyarasi , Ali Enas M. , Genena Marwa Azmy M. , Veeraraghavan Vishnupriya , Sekar Ramya , Sekar Ashok Kumar , Tejavat Sujatha , Barik Parthasarathi , Abdallah Basem M. 
Published: October 2024

Background

Phytochemicals possess a wide range of anti‐tumor properties, including the modulation of autophagy and regulation of programmed cell death. Autophagy is a critical process in cellular homeostasis and its dysregulation is associated with several pathological conditions, such as cancer, neurodegenerative diseases, and diabetes. In cancer, autophagy plays a dual role by either promoting tumor growth or suppressing it, depending on the cellular context. During autophagy, autophagosomes engulf cytoplasmic components such as proteins and organelles. LC3‐II (microtubule‐associated protein 1 light chain 3‐II) is an established marker of autophagosome formation, making it central to autophagy monitoring in mammals.

Objective

To explore the regulatory role of phytochemicals in LC3‐mediated autophagy and their potential therapeutic impact on cancer. The review emphasizes the involvement of autophagy in tumor promotion and suppression, particularly focusing on autophagy‐related signaling pathways like oxidative stress through the NRF2 pathway, and its implications for genomic stability in cancer development.

Methods

The review focuses on a comprehensive analysis of bioactive compounds including Curcumin, Celastrol, Resveratrol, Kaempferol, Naringenin, Carvacrol, Farnesol, and Piperine. Literature on these compounds was examined to assess their influence on autophagy, LC3 expression, and tumor‐related signaling pathways. A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to 2023. Studies were selected from prominent databases, focusing on their roles in cancer diagnosis and therapeutic interventions, particularly in relation to LC3‐mediated mechanisms.

Results

Phytochemicals have been shown to modulate autophagy through the regulation of LC3‐II levels and autophagic flux in cancer cells. The interaction between autophagy and other cellular pathways such as oxidative stress, inflammation, and epigenetic modulation highlights the complex role of autophagy in tumor biology. For instance, Curcumin and Resveratrol have been reported to either induce or inhibit autophagy depending on cancer type, influencing tumor progression and therapeutic responses.

Conclusion

Targeting autophagy through LC3 modulation presents a promising strategy for cancer therapy. The dual role of autophagy in tumor suppression and promotion, however, necessitates careful consideration of the context in which autophagy is induced or inhibited. Future research should aim to delineate these context‐specific roles and explore how phytochemicals can be optimized for therapeutic efficacy. Novel therapeutic strategies should focus on the use of bioactive compounds to fine‐tune autophagy, thereby maximizing tumor suppression and inducing programmed cell death in cancer cells.