Manzato Mariane Castro, de Santi Fabiane, da Silva André Acácio Souza, Beltrame Flávia L, Cerri Paulo S, Sasso-Cerri Estela
Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, School of Dentistry, São Paulo State University (Unesp), Araraquara, Brazil.
Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil.
J Anat. 2021 Jul;239(1):136-150. doi: 10.1111/joa.13408. Epub 2021 Mar 13.
Submandibular gland (SMG) is responsive to androgens via androgen receptor (AR). We verified whether cimetidine induces androgenic dysfunction in SMG, and evaluated the structural integrity, cell death and immunoexpression of actin, EGF and V-ATPase in androgen-deficient SMG. Male rats received cimetidine (CMTG) and control animals (CG) received saline. Granular convoluted tubules (GCTs) diameter and number of acinar cell nuclei were evaluated. TUNEL and immunofluorescence reactions for detection of AR, testosterone, actin, EGF and V-ATPase were quantitatively analysed. In CG, testosterone immunolabelling was detected in acinar and ductal cells cytoplasm. AR-immunolabelled nuclei were observed in acinar cells whereas ductal cells showed AR-immunostained cytoplasm, indicating a non-genomic AR action. In CMTG, the weak testosterone and AR immunoexpression confirmed cimetidine-induced androgenic failure. A high cell death index was correlated with decreased number of acinar cells, GCTs diameter and EGF immunoexpression under androgenic dysfunction. Actin immunofluorescence decreased in the SMG cells, but an increased and diffuse cytoplasmic V-ATPase immunolabelling was observed in striated ducts, suggesting a disruption in the actin-dependent V-ATPase recycling due to androgenic failure. Our findings reinforce the androgenic role in the maintenance of SMG histophysiology, and point to a potential clinical use of cimetidine against androgen-dependent glandular tumour cells.
下颌下腺（SMG）通过雄激素受体（AR）对雄激素产生反应。我们验证了西咪替丁是否会导致下颌下腺雄激素功能障碍，并评估了雄激素缺乏的下颌下腺中肌动蛋白、表皮生长因子（EGF）和V-ATP酶的结构完整性、细胞死亡及免疫表达情况。雄性大鼠接受西咪替丁（CMTG组），对照动物（CG组）接受生理盐水。评估了颗粒曲管（GCTs）的直径和腺泡细胞核的数量。对检测AR、睾酮、肌动蛋白、EGF和V-ATP酶的TUNEL和免疫荧光反应进行了定量分析。在CG组中，在腺泡和导管细胞的细胞质中检测到睾酮免疫标记。在腺泡细胞中观察到AR免疫标记的细胞核，而导管细胞显示AR免疫染色的细胞质，表明存在非基因组AR作用。在CMTG组中，睾酮和AR免疫表达较弱证实了西咪替丁诱导的雄激素功能衰竭。在雄激素功能障碍情况下，高细胞死亡指数与腺泡细胞数量减少、GCTs直径减小和EGF免疫表达降低相关。下颌下腺细胞中的肌动蛋白免疫荧光减少，但在纹状导管中观察到细胞质V-ATP酶免疫标记增加且呈弥漫性，这表明雄激素功能衰竭导致了肌动蛋白依赖性V-ATP酶循环受损。我们的研究结果强化了雄激素在维持下颌下腺组织生理学中的作用，并指出西咪替丁在对抗雄激素依赖性腺癌细胞方面的潜在临床应用。
