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Targeting the retinoic acid signaling pathway as a modern precision therapy against cancers
Kousalya Lavudi1,2,3, Shreya Madhav Nuguri4, Zianne Olverson1
1Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, United States.
Abstract:
Retinoic acid (RA) is a vital metabolite derived from vitamin A. RA plays a prominent role during development, which helps in embryological advancement and cellular differentiation. Mechanistically, RA binds to its definite nuclear receptors including the retinoic acid receptor and retinoid X receptor, thus triggering gene transcription and further consequences in gene regulation. This functional heterodimer activation later results in gene activation/inactivation. Several reports have been published related to the detailed embryonic and developmental role of retinoic acids and as an anti-cancer drug for specific cancers, including acute promyelocytic leukemia, breast cancer, and prostate cancer. Nonetheless, the other side of all-trans retinoic acid (ATRA) has not been explored widely yet. In this review, we focused on the role of the RA pathway and its downstream gene activation in relation to cancer progression. Furthermore, we explored the ways of targeting the retinoic acid pathway by focusing on the dual role of aldehyde dehydrogenase (ALDH) family enzymes. Combination strategies by combining RA targets with ALDH-specific targets make the tumor cells sensitive to the treatment and improve the progression-free survival of the patients. In addition to the genomic effects of ATRA, we also highlighted the role of ATRA in non-canonical mechanisms as an immune checkpoint inhibitor, thus targeting the immune oncological perspective of cancer treatments in the current era. The role of ATRA in activating independent mechanisms is also explained in this review. This review also highlights the current clinical trials of ATRA in combination with other chemotherapeutic drugs and explains the future directional insights related to ATRA usage.
Insights
All-trans retinoic acid (ATRA) shows promise in cancer treatment by modulating gene expression and immune responses. Targeting the retinoic acid pathway with ALDH inhibitors offers new therapeutic strategies for improved patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- Retinoic acid (RA), a vitamin A metabolite, is crucial for embryonic development and cellular differentiation.
- RA exerts its effects by binding to nuclear receptors (RAR/RXR) and regulating gene transcription.
- While RA's role in development and specific cancers is documented, its broader impact on cancer progression warrants further investigation.
Purpose of the Study:
- To review the role of the retinoic acid (RA) pathway in cancer progression.
- To explore targeting strategies involving RA and aldehyde dehydrogenase (ALDH) enzymes.
- To highlight ATRA's non-canonical mechanisms, including immune checkpoint inhibition and independent pathways.
Main Methods:
- Literature review focusing on RA pathway, gene activation, and cancer.
- Analysis of ALDH family enzymes in the context of RA targeting.
- Examination of ATRA's genomic and non-canonical effects on cancer and immunity.
Main Results:
- The RA pathway and its downstream gene activation are implicated in cancer progression.
- Targeting RA and ALDH enzymes can enhance anti-cancer treatment sensitivity and improve progression-free survival.
- ATRA exhibits immune checkpoint inhibitory functions and activates independent anti-cancer mechanisms.
Conclusions:
- The retinoic acid pathway presents a viable target for cancer therapy.
- Combination strategies involving ATRA and ALDH inhibitors show therapeutic potential.
- ATRA's multifaceted roles, including immune modulation, offer novel avenues for cancer treatment.
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