Division of Analytical Science, Korea Basic Science Institute, Daejeon 34133, Republic of Korea.
Department of Life Science and Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea.
J Microbiol Biotechnol. 2022 May 28;32(5):645-656. doi: 10.4014/jmb.2110.10019.
Gossypol, a natural phenolic aldehyde present in cotton plants, was originally used as a means of contraception, but is currently being studied for its anti-proliferative and anti-metastatic effects on various cancers. However, the intracellular mechanism of action regarding the effects of gossypol on pancreatic cancer cells remains unclear. Here, we investigated the anti-cancer effects of gossypol on human pancreatic cancer cells (BxPC-3 and MIA PaCa-2). Cell counting kit-8 assays, annexin V/propidium iodide staining assays, and transmission electron microscopy showed that gossypol induced apoptotic cell death and apoptotic body formation in both cell lines. RNA sequencing analysis also showed that gossypol increased the mRNA levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and activating transcription factor 3 (ATF3) in pancreatic cancer cell lines. In addition, gossypol facilitated the cleavage of caspase-3 via protein kinase RNA-like ER kinase (PERK), CHOP, and Bax/Bcl-2 upregulation in both cells, whereas the upregulation of ATF was limited to BxPC-3 cells. Finally, a three-dimensional culture experiment confirmed the successful suppression of cancer cell spheroids via gossypol treatment. Taken together, our data suggest that gossypol may trigger apoptosis in pancreatic cancer cells via the PERK-CHOP signaling pathway. These findings propose a promising therapeutic approach to pancreatic cancer treatment using gossypol.
棉酚，一种存在于棉花植物中的天然酚醛醛，最初被用作避孕手段，但目前正在研究其对各种癌症的抗增殖和抗转移作用。然而，关于棉酚对胰腺癌细胞的作用的细胞内机制尚不清楚。在这里，我们研究了棉酚对人胰腺癌细胞（BxPC-3 和 MIA PaCa-2）的抗癌作用。细胞计数试剂盒-8 分析、膜联蛋白 V/碘化丙啶染色分析和透射电子显微镜显示，棉酚诱导两种细胞系的凋亡细胞死亡和凋亡小体形成。RNA 测序分析还表明，棉酚增加了胰腺癌细胞系中 CCAAT/增强子结合蛋白同源蛋白（CHOP）和激活转录因子 3（ATF3）的 mRNA 水平。此外，棉酚通过蛋白激酶 RNA 样内质网激酶 (PERK)、CHOP 和 Bax/Bcl-2 的上调促进了两种细胞中 caspase-3 的切割，而 ATF 的上调仅限于 BxPC-3 细胞。最后，三维培养实验证实了棉酚处理成功抑制了癌细胞球体的生长。总之，我们的数据表明，棉酚可能通过 PERK-CHOP 信号通路触发胰腺癌细胞凋亡。这些发现为使用棉酚治疗胰腺癌提出了一种有前途的治疗方法。
