Rottlerin suppresses growth of human pancreatic tumors in nude mice, and pancreatic cancer cells isolated from Kras(G12D) mice

• Published in: Cancer letters Vol. 353; no. 1; p. 32
• Main Authors: Huang, Minzhao, Tang, Su-Ni, Upadhyay, Ghanshyam, Marsh, Justin L, Jackman, Christopher P, Srivastava, Rakesh K, Shankar, Sharmila
• Format: Journal Article
• Language: English
• Published: Ireland 10.10.2014
• Subjects: Acetophenones - pharmacology; Angiogenesis Inhibitors - pharmacology; Angiogenic Proteins - metabolism; Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Benzopyrans - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Genes, ras; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, Transgenic; Neovascularization, Pathologic; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - metabolism; Signal Transduction - drug effects; Time Factors; Tumor Burden - drug effects; Tumor Microenvironment; Xenograft Model Antitumor Assays; Cancer prevention; Akt; Rottlerin; Pancreatic cancer; Notch; Sonic Hedgehog
• ISSN: 1872-7980
• DOI: 10.1016/j.canlet.2014.06.021

The purpose of the study was to examine the molecular mechanisms by which rottlerin inhibited growth of human pancreatic tumors in Balb C nude mice, and pancreatic cancer cells isolated from Kras(G12D) mice. AsPC-1 cells were injected subcutaneously into Balb c nude mice, and tumor-bearing mice were treated with rottlerin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of components of Akt, Notch, and Sonic Hedgehog (Shh) pathways were measured by the immunohistochemistry, Western blot analysis, and/or q-RT-PCR. The effects of rottlerin on pancreatic cancer cells isolated from Kras(G12D) mice were also examined. Rottlerin-treated mice showed a significant inhibition in tumor growth which was associated with suppression of cell proliferation, activation of capase-3 and cleavage of PARP. Rottlerin inhibited the expression of Bcl-2, cyclin D1, CDK2 and CDK6, and induced the expression of Bax in tumor tissues compared to untreated control. Rottlerin inhibited the markers of angiogenesis (Cox-2, VEGF, VEGFR, and IL-8), and metastasis (MMP-2 and MMP-9), thus blocking production of tumorigenic mediators in tumor microenvironment. Rottlerin also inhibited epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Slug and Snail. Furthermore, rottlerin treatment of xenografted tumors or pancreatic cancer cells isolated from Kras(G12D) mice showed a significant inhibition in Akt, Shh and Notch pathways compared to control groups. These data suggest that rottlerin can inhibit pancreatic cancer growth by suppressing multiple signaling pathways which are constitutively active in pancreatic cancer. Taken together, our data show that the rottlerin induces apoptosis and inhibits pancreatic cancer growth by targeting Akt, Notch and Shh signaling pathways, and provide a new therapeutic approach with translational potential for humans.