Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China.
Mol Biol Rep. 2024 Jan 22;51(1):176. doi: 10.1007/s11033-023-09105-w.
Pancreatic cancer (PC) is a fatal human malignancy with a poor prognosis. Corosolic acid (CRA) is a triterpenoid, has been reported to have inhibitory effects on tumor growth. However, the role of CRA on PC has not been explored. Here, we aimed to uncover the molecular mechanisms of CRA in PC progression.
Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis and senescence were detected by cell counting kit-8 (CCK-8), LDH, flow cytometry and senescence associated-β-galactosidase (SA-β-gal) assay. Levels of relevant proteins and oxidative stress (OS) markers were evaluated by Western blot and enzyme-linked immunosorbent assay (ELISA). A xenograft tumor model was established to explore the in vivo effects of CRA on PC.
We found that CRA inhibited PC cell viability and promoted LDH release in a dose-dependent manner, but had no significant effect on human normal pancreatic ductal epithelial cells HPDE6C7. CRA increased OS-induced cell apoptosis and senescence in HAPC and SW1990 cells. And CRA decreased the levels of anti-apoptotic protein Bcl-2, and elevated the expression of pro-apoptotic protein Bax and senescence-associated proteins P21 and P53. Besides, CRA decreased tumor growth in xenograft models. Furthermore, CRA inactivated the Janus kinase-2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in HAPC and SW1990 cells. Functional experiments demonstrated that activation of the JAK2/STAT3 pathway by the JAK2 activator coumermycin A1 (C-A1) or the STAT3 activator colivelin (col) reduced the contribution effect of OS, apoptosis and senescence by CRA.
Taken together, our findings indicated that CRA exerted anti-cancer effects in PC by inhibiting the JAK2/STAT3 pathway.
胰腺癌（PC）是一种致命的人类恶性肿瘤，预后不良。熊果酸（CRA）是一种三萜类化合物，据报道对肿瘤生长具有抑制作用。然而，CRA 对 PC 的作用尚未得到探索。在这里，我们旨在揭示 CRA 在 PC 进展中的分子机制。
通过细胞计数试剂盒-8（CCK-8）、LDH、流式细胞术和衰老相关-β-半乳糖苷酶（SA-β-半乳糖苷）测定法检测细胞活力、乳酸脱氢酶（LDH）释放、细胞凋亡和衰老。通过 Western blot 和酶联免疫吸附试验（ELISA）评估相关蛋白和氧化应激（OS）标志物的水平。建立异种移植肿瘤模型以探索 CRA 对 PC 的体内作用。
我们发现 CRA 以剂量依赖性方式抑制 PC 细胞活力并促进 LDH 释放，但对人正常胰腺导管上皮细胞 HPDE6C7 没有明显影响。CRA 增加了 HAPC 和 SW1990 细胞中 OS 诱导的细胞凋亡和衰老。CRA 降低了抗凋亡蛋白 Bcl-2 的水平，并上调了促凋亡蛋白 Bax 和衰老相关蛋白 P21 和 P53 的表达。此外，CRA 减少了异种移植模型中的肿瘤生长。此外，CRA 在 HAPC 和 SW1990 细胞中使 Janus 激酶-2（JAK2）/信号转导和转录激活因子 3（STAT3）信号通路失活。功能实验表明，JAK2 激活剂库美霉素 A1（C-A1）或 STAT3 激活剂 colivelin（col）激活 JAK2/STAT3 通路可降低 CRA 对 OS、凋亡和衰老的贡献作用。
综上所述，我们的研究结果表明，CRA 通过抑制 JAK2/STAT3 通路在 PC 中发挥抗癌作用。
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