LB‐1 Exerts Antitumor Activity in Pancreatic Cancer by Inhibiting HIF‐1α and Stat3 Signaling. Issue 9 (September 2015)

• Record Type: Journal Article
• Authors: Niu, Fei; Li, Yan; Lai, Fang‐Fang; Ni, Lin; Ji, Ming; Jin, Jing; Yang, Han‐Ze; Wang, Chao; Zhang, Dong‐Ming; Chen, Xiao‐Guang
• Is Part Of: Journal of cellular physiology. Volume 230:Issue 9(2015:Sep.)
• Page Start: 2212
• Page End: 2223
• Publication Date: 2015-09
• Subjects: Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.24949
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Hypoxia is widely present in pancreatic cancer and subsequently causes the overexpression of hypoxia‐inducible factor‐1α (HIF‐1α) and signal transducer and activator of transcription‐3 (Stat3). HIF‐1α and Stat3 function cooperatively to regulate a number of downstream genes that are implicated in tumorigenesis. Thus, inhibition of HIF‐1α and Stat3 is a potential therapeutic strategy for pancreatic cancer. In this study, we explored how LB‐1, a novel triptolide (LA) derivative, exerted its antitumor effect through blockade of HIF‐1α and Stat3 signaling. Our data showed that LB‐1 was able to inhibit the proliferation and colony formation of Mia‐PaCa2 and SW1990 cells. LB‐1 suppressed HIF‐1α protein accumulation by promoting its proteasome degradation and reducing transactivation. Moreover, the silence of HIF‐1α by shRNA partially prevented the proliferation inhibition triggered by LB‐1. As expected, LB‐1 also decreased Stat3 protein accumulation and blocked the physical interactions between HIF‐1α/p300/phosphor‐Stat3 (p‐Stat3) at the pharmacological concentration to reduce VEGF expression, thereby hypoxia‐induced angiogenesis. In the Mia‐PaCa2 nude xenograft model, therapeutic treatment with LB‐1 significantly inhibited tumor growth and had minimal systemic toxicity compared to the mother drug LA. Furthermore, in accordance with in vitro results, HIF‐1α activation and Stat3 expression in tumors were blocked by LB‐1 through mTOR‐dependent pathway. Taken together, these results illustrate that, as a potent inhibitor of HIF‐1α and Stat3 signaling, LB‐1 exhibits antitumor effect and could be potentially used to treat pancreatic cancer. J. Cell. Physiol. 230: 2212–2223, 2015. © 2015 Wiley Periodicals, Inc.