Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

Abstract

Cumulative evidences(s) have established that the constitutive activation of STAT3 plays a pivotal role in the proliferation, survival, metastasis, and angiogenesis and thus can contribute directly to the pathogenesis of hepatocellular carcinoma (HCC). Thus, novel agents that can inhibit STAT3 activation have potential for both prevention and treatment of HCCs. The effect of celastrol on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of celastrol on the growth of human HCC xenograft tumors in athymic nu/nu mice was also examined. We observed that celastrol inhibited both constitutive and inducible STAT3 activation, and the suppression was mediated through the inhibition of activation of upstream kinases c-Src, as well as Janus-activated kinase-1 and -2. Vanadate treatment reversed the celastrol-induced modulation of STAT3, suggesting the involvement of a tyrosine phosphatase. The inhibition of STAT3 activation by celastrol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Celastrol also inhibited the proliferation and induced apoptosis in HCC cells. Finally, when administered intraperitoneally, celastrol inhibited STAT3 activation in tumor tissues and the growth of human HCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that celastrol exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. Cancer Prev Res; 5(4); 631-43. Ó2012 AACR.

Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway

“…A study by Peng et al (15) demonstrated that celastrol arrested the human monocytic leukemia cell line U937 in G0/G1. Another study, by Rajendran et al (16), revealed that celastrol causes the accumulation of human hepatocellular carcinoma cells in the sub-G1 phase of the cell cycle. Furthermore, G2/M arrest has been identified in human cervical carcinoma and prostate cancer cells (15,17).…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Natural agents, peptides, platinum compounds and other small molecules have been used to inhibit STAT3 activity in various tumor models including HCC [258]. Our group has identified number of STAT3 inhibitors including diosgenin, β-escin, γ-tocotrienol, butein, honokiol, and celastrol that can suppress growth and induce apoptosis in diverse HCC cell lines [259][260][261][262][263][264]. In addition, Chen and coworkers recently reported that a novel obatoclax derivative, SC-2001, can induce apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation [265].…”

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

“…To determine NF-kB and STAT3 activation, we conducted DNA-binding assay using TransAM NF-kB Kit or TransAM STAT3 Kit according to the manufacturer's instructions and as previously described (20,21). Briefly, 20 mg of nuclear proteins were added into a 96-well plate coated with an unlabeled oligonucleotide containing the consensus binding site for NF-kB (5 0 -GGGACTTTCC-3 0 ) or STAT3 (5 0 -TTCCCGGAA-3 0 ) and incubated for 1 hour.…”