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Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells
1School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Abstract:
All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RARγ is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RARγ antagonist inhibition of the action of RARγ led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RARγ, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells.
Insights
Targeting the retinoic acid pathway shows promise for cancer treatment. Inhibiting enzymes and receptors involved in all-trans retinoic acid synthesis and action can reduce cancer cell proliferation and induce apoptosis.
Area of Science:
- Oncology
- Developmental Biology
- Molecular Biology
Background:
- All-trans retinoic acid (ATRA) is a crucial developmental morphogen and a known teratogen.
- Cancer is fundamentally an error in cellular development, implicating pathways like ATRA signaling.
- Retinoic acid receptors (RARs) and enzymes in ATRA synthesis are implicated in various human cancers.
Purpose of the Study:
- To investigate the role of the retinoic acid pathway in cancer development and progression.
- To evaluate the therapeutic potential of targeting ATRA synthesis enzymes and RARs in different cancer types.
- To explore novel strategies for eradicating cancer stem cells via the retinoic acid pathway.
Main Methods:
- Examined the expression of cytosolic aldehyde dehydrogenases in human cancers.
- Assessed the effects of inhibiting these enzymes on cancer cell proliferation and apoptosis.
- Investigated the oncogenic role of RARγ in specific cancers.
- Utilized pan-RAR and RARγ antagonists to study their effects on cancer stem cells.
- Evaluated the impact of acacetin, an RARγ inhibitor, on hepatocellular carcinoma cells.
Main Results:
- Inhibition of ATRA synthesis enzymes reduced proliferation and induced apoptosis in multiple cancer cell lines (lung, ovarian, prostate, squamous, uterine) and sensitized others to chemotherapy.
- RARγ was identified as an oncogene in AML, cholangiocarcinoma, colorectal, clear cell renal cell, hepatocellular, pancreatic ductal adenocarcinoma, prostate, and ovarian cancers.
- Inhibition of RARγ signaling led to necroptosis in prostate and pediatric brain tumor cancer stem cells.
- Acacetin treatment decreased hepatocellular carcinoma cell growth and induced apoptosis.
Conclusions:
- The retinoic acid pathway, including ATRA synthesis enzymes and RARs, represents a viable target for cancer therapy.
- Targeting RARγ and its downstream signaling pathways holds significant therapeutic potential, particularly for cancer stem cell eradication.
- Interference with the retinoic acid pathway offers a promising strategy for developing novel anti-cancer drugs.
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