GV1001, a 16-amino acid fragment of the human telomerase reverse transcriptase catalytic subunit (hTERT), has been developed as an injectable formulation of cancer vaccine. Here, we revealed for the first time that GV1001 is a novel ligand for gonadotropin-releasing hormone receptor (GnRHR). The docking prediction for GV1001 against GnRHR showed high binding affinity. Binding of GV1001 to GnRHR stimulated the Gαs-coupled cAMP signaling pathway and antagonized Gαq-coupled Ca2+ release by leuprolide acetate (LA), a GnRHR agonist. Repeated injection of GV1001 attenuated both serum testosterone level and seminal vesicle weight via desensitization of hypothalamic–pituitary–gonadal (HPG) axis. We then tested whether GV1001 has an inhibitory effect on tumor growth of LNCaP cells, androgen receptor–positive human prostate cancer (PCa) cells. GV1001 significantly inhibited tumor growth and induced apoptosis in LNCaP-implanted xenografts. Interestingly, mRNA expressions of matrix metalloproteinase 2 and matrix metalloproteinase 9 were suppressed by GV1001, but not by LA. Moreover, GV1001 significantly inhibited the proliferation and migration of PCa cells and induced apoptosis in a concentration-dependent manner. Our findings suggest that GV1001 functions as a biased GnRHR ligand to selectively stimulate the Gαs/cAMP pathway, with anti-proliferative and anti-migratory effects on human PCa.
Ji Won Kim, Dharmendra K Yadav, Soo Jin Kim, Moo-Yeol Lee, Jung-Min Park, Bum Seok Kim, Mi-hyun Kim, Hyeung-geun Park and Keon Wook Kang
Seog Yun Park, Yuh-S Jung, Chang Hwan Ryu, Chang Yoon Lee, You Jin Lee, Eun Kyung Lee, Seok-Ki Kim, Tae Sung Kim, Tae Hyun Kim, Jeyun Jang, Daeyoon Park, Seung Myung Dong, Jae-Goo Kang, Jin Soo Lee and Junsun Ryu
We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11–8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68–15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03–8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients.