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Luteolin modulates gene expression related to steroidogenesis, apoptosis, and stress response in rat LC540 tumor Leydig cells

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Abstract

In males, androgens are mainly produced by Leydig cells from the testis. A critical and highly regulated step of steroidogenesis involves the importation of cholesterol within the mitochondria by the steroidogenic acute regulatory (STAR) protein. During aging, STAR protein levels in Leydig cells gradually decrease, leading to a reduced entry of cholesterol into mitochondria and lower testosterone production. In addition to preserving its steroidogenic capacity, tumor Leydig cells can also be excellent models for evaluating the mechanisms of action of anticancer agents. In this study, we examined whether polyphenolics having structural similarities to luteolin could promote steroidogenic and cancer-related gene expressions within rat L540 tumor Leydig cells. In this cell model, luteolin activated Star expression and increased progesterone as well as testosterone productions. Interestingly, luteolin decreased gene expression related to cholesterol biosynthesis, possibly inhibiting membrane synthesis and cell proliferation. In addition, increased expression of genes such as Fas, Cdkn1a, Atp7b, and Tp53, as well as increased accumulation of cleaved caspase 3 and PARP, in response to luteolin treatment indicates that apoptosis is being activated. Luteolin also modulated the expression of genes involved in stress response, such as glutathione-S transferases Gsta1 and Gstt2, and the unfolded protein response. Thus, dietary luteolin may be effective in Leydig cell tumor chemoprevention and in maintaining steroidogenesis in aging males.

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Abbreviations

Atp7b:

ATPase copper transporting beta

bp:

Base pair

Casp3:

Caspase 3

Cdkn1a:

Cyclin-dependent kinase inhibitor 1A (P21, WAF1)

Cyp11a1:

Cholesterol side-chain cleavage enzyme

Cyp17a1:

Steroid 17-alpha-hydroxylase/17,20 lyase enzyme

Derl3:

Derlin 3

Eif4h:

Eukaryotic translation initiation factor 4H

ELISA:

Enzyme-linked immunosorbent assay

Fas:

Fas cell surface death receptor

Gsta1:

Glutathione S-transferase alpha 1

Gstt2:

Glutathione S-transferase theta 2

Hsd17b7:

Hydroxysteroid 17-beta dehydrogenase 7

Hsd3b1:

Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 enzyme

LH:

Luteinizing hormone

Lss:

Lanosterol synthase

Mdm2:

MDM2 proto-oncogene

Nfe2:

Nuclear factor, erythroid 2

Nsdhl:

NAD(P) dependent steroid dehydrogenase-like

PARP:

Poly (ADP-ribose) polymerase

Rpl19:

Ribosomal protein L19

Star:

Steroidogenic acute regulatory protein

Tm7sf3:

Transmembrane 7 superfamily member 3

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Acknowledgments

We thank Olivier Dangles (UMR408 INRA–UAPV,SQPO, Chimie des Antioxydants, Université d’Avignon) for his help in the synthesis of luteolinidin.

Funding

The current work was funded by the New Brunswick Innovation Foundation (NBIF) (#CV2017 to L.J.M.), the Beatrice Hunter Cancer Research Institute/New Brunswick Health Research Foundation (2017-Seed to L.J.M.) and the Natural Sciences and Engineering Research Council (NSERC) of Canada (#386557 to L.J.M.; #04560 to M.T.).

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Couture, R., Mora, N., Al Bittar, S. et al. Luteolin modulates gene expression related to steroidogenesis, apoptosis, and stress response in rat LC540 tumor Leydig cells. Cell Biol Toxicol 36, 31–49 (2020). https://doi.org/10.1007/s10565-019-09481-9

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