Antagonizing RARγ Drives Necroptosis of Cancer Stem Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 May 14

PMID 35563205

Authors

Geoffrey Brown

Affiliations

Soon will be listed here.

Abstract

There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare cancer stem cells. Therapeutics that target cancer stem cells may also provide a cure for cancer. There are two rationales for targeting the retinoic acid receptor (RAR)γ. First, RARγ is expressed selectively within primitive cells. Second, RARγ is a putative oncogene for a number of human cancers, including cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, renal and hepatocellular carcinomas. Prostate cancer cells depend on active RARγ for their survival. Antagonizing all RARs caused necroptosis of prostate and breast cancer stem cell-like cells, and the cancer stem cells that gave rise to neurospheres from pediatric patients' primitive neuroectodermal tumors and an astrocytoma. As tested for prostate cancer, antagonizing RARγ was sufficient to drive necroptosis. Achieving cancer-selectively is a longstanding paradigm for developing new treatments. The normal prostate epithelium was less sensitive to the RARγ antagonist and pan-RAR antagonist than prostate cancer cells, and fibroblasts and blood mononuclear cells were insensitive. The RARγ antagonist and pan-RAR antagonist are promising new cancer therapeutics.

Citing Articles

Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy.

Liang H, Zhou B, Li P, Zhang X, Zhang S, Zhang Y Ann Med. 2024; 57(1):2442067.

PMID: 39711287 PMC: 11703425. DOI: 10.1080/07853890.2024.2442067.

Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ.

Powala K, Zolek T, Brown G, Kutner A Int J Mol Sci. 2024; 25(12).

PMID: 38928275 PMC: 11203493. DOI: 10.3390/ijms25126568.

Deregulation of All- Retinoic Acid Signaling and Development in Cancer.

Brown G Int J Mol Sci. 2023; 24(15).

PMID: 37569466 PMC: 10419198. DOI: 10.3390/ijms241512089.

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II.

Kutner A, Brown G, Kallay E Int J Mol Sci. 2023; 24(6).

PMID: 36982694 PMC: 10053869. DOI: 10.3390/ijms24065621.

Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells.

Brown G Int J Mol Sci. 2023; 24(3).

PMID: 36768694 PMC: 9916838. DOI: 10.3390/ijms24032373.

References

Holyoake T, Jiang X, Eaves C, Eaves A . Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999; 94(6):2056-64. View

Xu Q, Jitkaew S, Choksi S, Kadigamuwa C, Qu J, Choe M . The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited. Nat Commun. 2017; 8(1):425. PMC: 5583178. DOI: 10.1038/s41467-017-00496-6. View

Liu B, Yan L, Zhou M . Target selection of CAR T cell therapy in accordance with the TME for solid tumors. Am J Cancer Res. 2019; 9(2):228-241. PMC: 6405971. View

Graham S, Jorgensen H, Allan E, Pearson C, Alcorn M, Richmond L . Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002; 99(1):319-25. DOI: 10.1182/blood.v99.1.319. View

Namekawa T, Ikeda K, Horie-Inoue K, Inoue S . Application of Prostate Cancer Models for Preclinical Study: Advantages and Limitations of Cell Lines, Patient-Derived Xenografts, and Three-Dimensional Culture of Patient-Derived Cells. Cells. 2019; 8(1). PMC: 6357050. DOI: 10.3390/cells8010074. View

Rosolen A, Favaretto G, Masarotto G, Cavazzana A, Zanesco L, Frascella E . Effects of all-trans retinoic acid and interferon alpha in peripheral neuroectodermal tumor cell cultures and xenografts. Int J Oncol. 1998; 13(5):943-9. DOI: 10.3892/ijo.13.5.943. View

Culig Z, Klocker H, Eberle J, Kaspar F, Hobisch A, Cronauer M . DNA sequence of the androgen receptor in prostatic tumor cell lines and tissue specimens assessed by means of the polymerase chain reaction. Prostate. 1993; 22(1):11-22. DOI: 10.1002/pros.2990220103. View

Knudsen K, Penning T . Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010; 21(5):315-24. PMC: 2862880. DOI: 10.1016/j.tem.2010.01.002. View

Huynh T, Sultan M, Vidovic D, Dean C, Cruickshank B, Lee K . Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells. Sci Rep. 2019; 9(1):9414. PMC: 6602962. DOI: 10.1038/s41598-019-45982-7. View

10.

Quintana E, Shackleton M, Sabel M, Fullen D, Johnson T, Morrison S . Efficient tumour formation by single human melanoma cells. Nature. 2008; 456(7222):593-8. PMC: 2597380. DOI: 10.1038/nature07567. View

11.

HEYMAN R, Mangelsdorf D, Dyck J, Stein R, Eichele G, Evans R . 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992; 68(2):397-406. DOI: 10.1016/0092-8674(92)90479-v. View

12.

Farboud B, Hauksdottir H, Wu Y, Privalsky M . Isotype-restricted corepressor recruitment: a constitutively closed helix 12 conformation in retinoic acid receptors beta and gamma interferes with corepressor recruitment and prevents transcriptional repression. Mol Cell Biol. 2003; 23(8):2844-58. PMC: 152560. DOI: 10.1128/MCB.23.8.2844-2858.2003. View

13.

Biswas A, Han S, Tai Y, Ma W, Coker C, Quinn S . Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer. Cancer Discov. 2022; 12(4):1002-1021. PMC: 8983473. DOI: 10.1158/2159-8290.CD-21-0910. View

14.

Pasquali D, Thaller C, Eichele G . Abnormal level of retinoic acid in prostate cancer tissues. J Clin Endocrinol Metab. 1996; 81(6):2186-91. DOI: 10.1210/jcem.81.6.8964849. View

15.

Greaves M . Evolutionary determinants of cancer. Cancer Discov. 2015; 5(8):806-20. PMC: 4539576. DOI: 10.1158/2159-8290.CD-15-0439. View

16.

Chiu H, Fischman D, Hammerling U . Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation. FASEB J. 2008; 22(11):3878-87. PMC: 2574026. DOI: 10.1096/fj.08-112375. View

17.

Chen Y, Clarke O, Kim J, Stowe S, Kim Y, Assur Z . Structure of the STRA6 receptor for retinol uptake. Science. 2016; 353(6302). PMC: 5114850. DOI: 10.1126/science.aad8266. View

18.

Sanz M, Fenaux P, Tallman M, Estey E, Lowenberg B, Naoe T . Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019; 133(15):1630-1643. PMC: 6509567. DOI: 10.1182/blood-2019-01-894980. View

19.

Bosch A, Bertran S, Lu Y, Garcia A, Jones A, Dawson M . Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis. Breast Cancer Res. 2012; 14(4):R121. PMC: 3680916. DOI: 10.1186/bcr3247. View

20.

Trasino S, Harrison E, Wang T . Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in the androgen-responsive human prostate cancer cell line LNCaP. Exp Biol Med (Maywood). 2007; 232(6):762-71. View