Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling.
Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling.
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DOI：
10.1016/j.canlet.2013.07.037
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发表时间：
2013-12-01
期刊：
影响因子：
9.7
通讯作者：
Jain, Maneesh
中科院分区：
文献类型：
--
作者：
Macha, Muzafar A.;Rachagani, Satyanarayana;Gupta, Suprit;Pai, Priya;Ponnusamy, Moorthy P.;Batra, Surinder K.;Jain, Maneesh
与现有化疗剂相关的疗效不足、高毒性和耐药性要求对高度侵袭性胰腺癌（PC）的新治疗策略的需求。Guggulsterone（GS）对多种癌细胞表现出有效的抗增殖作用，并已成为用于补充或预防性癌症治疗的有吸引力的候选物。然而，关于GS在PC中的治疗潜力的知识仍然是有限的，需要探索。本文研究了GS对PC细胞生长、运动和侵袭的影响，并阐明了GS抗肿瘤作用的分子机制。用GS处理Capan 1和CD 18/HPAF PC细胞导致剂量和时间依赖性生长抑制和集落形成减少。此外，GS处理诱导细胞凋亡和细胞周期阻滞，如通过Annexin-V测定和FACS分析所评估的。GS处理后细胞凋亡增加伴随Bad去磷酸化及其易位到线粒体，Caspase-3活化增加，Cyclin D1，Bcl-2和xIAP表达降低。此外，GS处理通过破坏细胞骨架组织、抑制FAK和Src信号传导的活化以及降低MMP 9表达来降低PC细胞的运动性和侵袭性。更重要的是，GS处理通过抑制Jak/STAT途径通过转录调节降低Capan 1和CD 18/HPAF细胞中粘蛋白MUC 4的表达。总之，我们的研究结果支持GS作为致死性PC的潜在治疗剂的效用。
Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive pancreatic cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.
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