SZ-685C inhibits the growth of non-functioning pituitary adenoma by down-regulating miR-340-3p and inducing autophagy

Xin Wang; Zhong-Yu Wang; Hui-Tong Chen; Yu-You Luo; Si-Yuan Li; Xiong-Ming Luo; Jun-Hua Yang; Yu-Xin Ma; Xiao-Bao Jin; Jing Liu; Zong-Ming Wang

doi:10.1016/j.heliyon.2024.e37230

SZ-685C inhibits the growth of non-functioning pituitary adenoma by down-regulating miR-340-3p and inducing autophagy

Heliyon. 2024 Aug 30;10(17):e37230. doi: 10.1016/j.heliyon.2024.e37230. eCollection 2024 Sep 15.

Authors

Xin Wang¹, Zhong-Yu Wang¹, Hui-Tong Chen¹, Yu-You Luo¹, Si-Yuan Li¹, Xiong-Ming Luo^{2

3}, Jun-Hua Yang¹, Yu-Xin Ma¹, Xiao-Bao Jin^{1

3}, Jing Liu¹, Zong-Ming Wang⁴

Affiliations

¹ Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
² School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
³ Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
⁴ Pituitary Tumor Center, Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

Abstract

Background: SZ-685C, an anthracycline compound derived from the mangrove endophytic fungus Halorosellinia sp. (No. 1403) collected from the South China Sea, has shown strong anticancer activities. Non-functioning pituitary adenomas (NFPAs) are a type of tumor that can be challenging to manage clinically and have a significant unmet medical need. Our research has found that SZ-685C showed an inhibitory effect on the viability, migration ability, and proliferation ability of a human non-functioning pituitary tumor-derived folliculostellate (PDFS) cell line.

Methods: SZ-685C was prepared and purified from the mangrove endophytic fungus No. 1403. PDFS cells were exposed to SZ-685C, and the effect of SZ-685C on PDFS cells was evaluated. RNA sequencing was used to analyze the miRNA expression profile in PDFS cells of the control group and SZ-685C-treated group. Quantitative polymerase chain reaction (qPCR) was performed to verify the expression of selected miR-340-3p. The effects of SZ-685C on PDFS cells after overexpression of miR-340-3p were evaluated. Dual-luciferase reporter assays showed PPP1CB is a direct target of miR-340-3p. Finally, the action pathway of the selected miR-340-3p was predicted and evaluated through bioinformatics analysis.

Results: SZ-685C reduced cell viability in PDFS cells, accompanied by inhibition of migration ability and proliferation ability. The IC50 value for 24 h is 9.144 ± 0.991 μM, and for 48 h is 4.635 ± 0.551 μM. SZ-685C increased the protein levels of Beclin 1, the ratio of LC3-II to LC3-I, and LAMP-1, and down-regulated p62. MiRNA sequencing and further validation showed that miR-340-3p significantly decreased in PDFS cells treated with SZ-685C. After overexpression of miR-340-3p, the inhibition of viability, migration ability, proliferation ability, and autophagy-promoting effect of SZ-685C on PDFS cells were weakened. SZ-685C caused a decrease in PPP1CB expression and activation of the ERK pathway in PDFS cells, and this trend was reversed after overexpression of miR-340-3p.

Conclusions: SZ-685C downregulates the expression of miR-340-3p in PDFS cells, thereby reducing the expression of PPP1CB and activating the ERK pathway to promote autophagic cell death, leading to inhibition of PDFS cell growth.

Keywords: Autophagy; Non-functioning pituitary adenoma; PDFS; SZ-685C; miR-340-3p.