CRABP1 and CRABP2 Protein Levels Correlate with Each Other but Do Not Correlate with Sensitivity of Breast Cancer Cells to Retinoic Acid

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Adel D. Enikeev¹, Andrey V. Komelkov^1,a*, Maria E. Axelrod¹, Sergey A. Galetsky¹, Sergey A. Kuzmichev¹, and Elena M. Tchevkina¹

¹Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia

^* To whom correspondence should be addressed.

Received August 17, 2020; Revised September 30, 2020; Accepted September 30, 2020

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Retinoic acid (RA) binding proteins, CRABP1 and CRABP2, are molecular chaperones that mediate intracellular activity of RA, the key promoter of cell differentiation with tumor suppressor activity. One of the main functions of CRABP2 is delivery and transfer of RA to the nuclear receptors RAR/RXR, which leads to activation of the transcription of a wide range of retinoid-responsive genes. The functions of CRABP1 are less studied but are apparently associated with sequestration of RA in cytoplasm and limitation of its transcriptional activity, suggesting involvement of this protein in the development of RA resistance. The mechanisms regulating activity of CRABP1 are also poorly understood. Comparison of the CRABP1 level in tumor cell lines of various origins, performed for the first time here, showed absence of the CRABP1 protein in the cell lines of tumors considered to be RA-resistant, and pronounced production of this protein in the RA-sensitive cells. However, analysis carried out with a panel of breast cancer cell lines with different levels of RA-sensitivity showed that there was no correlation between the production of CRABP1 protein and the sensitivity of the cells to RA. At the same time, we found strong correlation between the expression of CRABP1 and CRABP2 proteins in all studied cell types, regardless of their origin and RA-sensitivity/resistance. Moreover, suppression of the CRABP1 level in both RA-sensitive and RA-resistant cells was shown in the cells with cells with knockdown of CRABP2 gene. The revealed CRABP2-dependent regulation of CRABP1 production is a new mechanism of the intracellular retinoic signaling system.

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KEY WORDS: retinoic acid, retinoic acid binding proteins, ATRA, CRABP1, CRABP2, proliferation, expression regulation

DOI: 10.1134/S0006297921020103

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