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Transmembrane BAX Inhibitor Motif-6 (TMBIM6) protects against cisplatin-induced testicular toxicity

STUDY QUESTION
Is the Transmembrane BAX Inhibitor Motif-6 (TMBIM6) involved in the molecular mechanism by which cisplatin causes reproductive toxicity?

SUMMARY ANSWER
TMBIM6 protects against cisplatin-induced testicular toxicity through up-regulation of heme oxygenase-1 (HO-1),-which maintains the levels of steroidogenic enzymes by decreaseing oxidative stress in the endoplasmic reticulum (ER).

WHAT IS KNOWN ALREADY
Testosterone production is highly suppressed as a main complication of cisplatin (cis-diamminedichloroplatinum) anticancer therapy.

STUDY DESIGN, SIZE, DURATION
Groups of seven wild type or Tmbim6 KO C57BL/6J mice were given a single i. p., injection of cisplatin (30 mg/kg body wt) and testis and serum were collected 3 days later. Tmbim6-lentivirus-mediated testicular expression-rescued KO mice were analyzed to confirm function was restored. Tmbim6-over expressing TM3 mouse Leydig cells were exposed to cisplatin in vitro.

PARTICIPANTS/MATERIALS, SETTING, METHODS
After collection of the specimens serum testosterone level and testicular weight and structure were compared between the groups. Quantitative PCR, immunoblot, and assays for ROS, HO-1 activity and protein disulfide isomerase (PDI) carbonylation were performed.

MAIN RESULTS AND THE ROLE OF CHANCE
Phospho protein kinase B (p-Akt), nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), and its downstream gene product HO-1 and the levels of testosterone synthesis-associated enzymes, including steroidogenic acute regulatory protein (StAR), a rate limiting enzyme for testosterone production, were significantly expressed in the presence of Tmbim6 and maintained after cisplatin treament. Excessive post-translational oxidation of protein disulfide isomerase (PDI), altered folding capacitance and ROS accumulation, and ER stress were also decreased in the presence of Tmbim6. Higher levels of ER stress and protein hypercarbonylation were consistently observed in KO testis, compared with WT testis. In the Tmbim6 KO mice, lentivirus-mediated testicular expression of Tmbim6 rescued the above phenotypes. Furthermore, the protective role of Tmbim6 against testicular toxicity was consistently shown in Tmbim6-overexpressing TM3 Leydig cells (testosterone producing cells). We conclude that TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 and enhancing ER folding capacitance.

LIMITATIONS, REASONS FOR CAUTION
This study was performed using a short, 3-day cisplatin treatment condition. Therefore, the results need to be cautiously interpreted with regard to cisplatin-associated chronic toxicity. Moreover, to determine the clinical relevance of the role of TMBIM6, further studies in testicular cancer are needed.

WIDER IMPLICATIONS OF THE FINDINGS
Cisplatin-associated ER stress and redox imbalance might be implicated as toxicity mechanisms associated with anticancer therapy.

STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the National Research Foundation of Korea (2015R1A2A1A13001849). The authors have no competing interests to disclose.

Keywords: TMBIM6, cisplatin, HO-1, ER redox, ER stress, testicular toxicity


Hyun-Kyoung Kim, Raj Kumar Yadav, Kashi Raj Bhattarai ,Han-Wool Jung, Hyung-Ryong Kim, Han-Jung Chae
Department of Pharmacology and Institute of New Drug Development, Chonbuk National University, Jeonju 54689, Republic of Korea
Human Reproduction, Volume 33, Issue 3, 1 March 2018, Pages 378–389
DOI: https://doi.org/10.1093/humrep/dex381

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