Park Min Ju, Kim Yoon Hee
Department of Food and Nutrition, College of Engineering, Daegu University, Gyeongsan-Si, Gyeongsangbuk-do, Republic of Korea.
Cancer Rep (Hoboken). 2024 Dec;7(12):e70074. doi: 10.1002/cnr2.70074.
Pancreatic cancer is difficult to treat early as it has no early symptoms. The presence of sulforaphane (SFN) in cruciferous vegetables has been found to possess anti-cancer effects in gastric and colon cancers. Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, plays a significant role in pancreatic cancer progression, influencing tumor growth, metastasis, and treatment resistance. Targeting GSK-3β has shown potential to enhance the efficacy of chemotherapy. However, the mechanism underlying the anticancer effects of SFN on pancreatic cancer through GSK-3β is unclear.
In this study, we examined the anticancer effects of SFN in human pancreatic cancer cell line Mia PaCa-2 and evaluated its molecular mechanisms with respect to the GSK-3β-related pathway.
SFN increased the protein expression of the phosphorylated form of GSK3β (Ser9). In the Wingless Int-1 homolog/β-catenin pathway, GSK3β induced apoptosis by phosphorylating β-catenin. However, in mutant Kirsten rat sarcoma viral oncogene homolog-like-dependent cells such as Mia PaCa-2, GSK3β was suppressed and the β-catenin level was increased, thus inducing apoptosis. Indeed, SFN increased the protein expression of β-catenin in the cytoplasm and nucleus. Subsequently, we measured the level of cMyc, the target gene of β-catenin. SFN decreased cMyc expression despite an increase in the β-catenin. We measured the expression of nuclear factor (NF)-κB, a downstream factor of GSK3β and an upstream factor of cMyc. SFN decreased the expression of NF-κB and cMyc, indicating that SFN inhibits cell proliferation by suppressing the GSK3β/NF-κB/cMyc pathway. As the suppression of NF-κB results in a decrease in B-cell lymphoma 2 (BCL-2) which is the anti-apoptotic gene, we tested the effect of SFN in the expression of BCL-2. SFN inhibited the expression of BCL-2 and increased the ratio of the apoptotic regulator gene BCL-2 associated X (BAX), where SFN induced the cleaved cysteine aspartase-3 and poly-adenosine diphosphate ribose polymerase.
These results indicate that SFN may have therapeutic potential in the inhibition of pancreatic cancer.
胰腺癌早期难以治疗，因为它没有早期症状。十字花科蔬菜中存在的萝卜硫素（SFN）已被发现对胃癌和结肠癌具有抗癌作用。糖原合酶激酶-3β（GSK-3β）是一种丝氨酸/苏氨酸激酶，在胰腺癌进展中起重要作用，影响肿瘤生长、转移和治疗耐药性。靶向GSK-3β已显示出增强化疗疗效的潜力。然而，SFN通过GSK-3β对胰腺癌产生抗癌作用的机制尚不清楚。
在本研究中，我们检测了SFN对人胰腺癌细胞系Mia PaCa-2的抗癌作用，并评估了其与GSK-3β相关途径的分子机制。
SFN增加了GSK3β（Ser9）磷酸化形式的蛋白表达。在无翅型MMTV整合位点家族成员1/β-连环蛋白（Wnt/β-catenin）途径中，GSK3β通过磷酸化β-连环蛋白诱导细胞凋亡。然而，在诸如Mia PaCa-2等依赖于突变型Kirsten大鼠肉瘤病毒癌基因同源物的细胞中，GSK3β受到抑制，β-连环蛋白水平升高，从而诱导细胞凋亡。事实上，SFN增加了细胞质和细胞核中β-连环蛋白的蛋白表达。随后，我们检测了β-连环蛋白靶基因cMyc的水平。尽管β-连环蛋白增加，但SFN降低了cMyc的表达。我们检测了GSK3β的下游因子和cMyc的上游因子核因子（NF）-κB的表达。SFN降低了NF-κB和cMyc 的表达，表明SFN通过抑制GSK3β/NF-κB/cMyc途径抑制细胞增殖。由于NF-κB的抑制导致抗凋亡基因B细胞淋巴瘤-2（BCL-2）的减少，我们检测了SFN对BCL-2表达的影响。SFN抑制了BCL-2的表达，并增加了凋亡调节基因Bcl-2相关X蛋白（BAX）的比例，其中SFN诱导了半胱氨酸天冬氨酸蛋白酶-3和聚腺苷二磷酸核糖聚合酶的裂解。
这些结果表明SFN在抑制胰腺癌方面可能具有治疗潜力。
