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

  • Roxanne Couture
  • Nathalie Mora
  • Sheiraz Al Bittar
  • Mustapha Najih
  • Mohamed Touaibia
  • Luc J. MartinEmail author
Original Article

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.

Keywords

Quercetin Luteolin Apigenin Genistein Luteolinidin Leydig 

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

Notes

Acknowledgments

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

Funding information

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.).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. 1.Biology DepartmentUniversité de MonctonMonctonCanada
  2. 2.UMR408 INRA–UAPV, SQPO, Chimie des AntioxydantsUniversité d’Avignon, Campus Jean-Henri Fabre, Pôle AgrosciencesAvignonFrance
  3. 3.Chemistry and Biochemistry DepartmentUniversité de MonctonMonctonCanada

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