Abstract 412: Tanshinone analog induces ER stress mediated growth suppression via inhibition of MYC and E2F pathways in prostate cancer cells.

Abstract Prostate cancer (PCa) is the most common malignancy among men in developed countries, and its increasing incidence is closely associated with the rising prevalence of obesity and metabolic syndrome. Our previous studies demonstrated that the Tanshinone analog (TA) enhances ATF3 expression, inhibits adipogenesis and lipogenesis, and promotes adipocyte browning. Although both native Tanshinones and their analogs have been reported to influence PCa cell growth, the underlying mechanisms remain incompletely understood. This study aimed to investigate whether TA regulates the growth of PCa cells through modulation of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and E2F family-related pathways. Using androgen-dependent LNCaP cells and androgen-independent DU145 and PC3 cells as PCa models, we examined the effects of TA on cell growth and associated signaling pathways. TA treatment significantly reduced cell numbers in all three PCa cell lines in a dose-dependent manner, as determined by hemocytometer counting. Colony formation assays confirmed a marked decrease in both colony number and diameter, indicating strong anti-tumor activity. Gene Set Enrichment Analysis (GSEA) of RNA sequencing data revealed that TA markedly suppressed MYC- and E2F target-associated pathways in LNCaP and DU145 cells. In contrast, differential gene expression (DEG) enrichment analysis showed upregulation of ER stress-related pathways, which was further validated by qPCR and western blot analyses of ER stress markers including PERK, ATF6, IRE1α, ATF4, and CHOP. Additionally, TA reduced androgen receptor protein levels and its nuclear translocation in LNCaP cells. In vivo, TA treatment (10 mg/kg, i.p., twice weekly for six weeks) significantly reduced tumor growth in DU145 xenograft-bearing immunodeficient mice compared with controls (2.30 ± 0.23 g vs. 3.53 ± 0.43 g; P < 0.05). TA treatment also decreased lung weight relative to the control group (0.21 ± 0.03 g vs. 0.36 ± 0.06 g; P < 0.05), indicating effective inhibition of lung metastasis. Histological analysis further confirmed that both primary prostate tumors and metastatic lung tumors were smaller in the TA-treated group than in controls. Moreover, there was no biochemical evidence of hepatotoxicity or nephrotoxicity, as hepatic (ALT, AST) and renal (BUN, creatinine) biomarkers remained unchanged after six weeks of TA treatment. In conclusion, TA exerts multiple anti-tumor effects in PCa by activating ER stress and suppressing MYC- and E2F-related signaling. These findings highlight TA as a promising therapeutic candidate for prostate cancer treatment. Citation Format: Ching-Feng Cheng, Hui-Chen Ku, Guo-Zhou Cheng. Tanshinone analog induces ER stress mediated growth suppression via inhibition of MYC and E2F pathways in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 412.