Open Accessα-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (KrasG12D, and KrasG12D/tp53R270H) mice
Author(s) -
Raj Kumar Verma,
Wei Yu,
Anju Shrivastava,
Sharmila Shankar,
Rakesh Srivastava
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep32743
Subject(s) - homeobox protein nanog , cancer research , pancreatic cancer , cyclopamine , cancer stem cell , gli1 , sox2 , cd44 , stem cell , carcinogenesis , metastasis , biology , chemistry , hedgehog signaling pathway , microbiology and biotechnology , cancer , transcription factor , cell , signal transduction , embryonic stem cell , induced pluripotent stem cell , biochemistry , genetics , gene
Activation of sonic hedgehog (Shh) in cancer stem cell (CSC) has been demonstrated with aggressiveness of pancreatic cancer. In order to enhance the biological activity of α-mangostin, we formulated mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which they inhibit human and KC mice (Pdx Cre ;LSL-Kras G12D ) pancreatic CSC characteristics in vitro , and pancreatic carcinogenesis in KPC (Pdx Cre ;LSLKras G12D ;LSL-Trp53 R172H ) mice. Mang-NPs inhibited human and Kras G12D mice pancreatic CSC characteristics in vitro . Mang-NPs also inhibited EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Slug, and pluripotency maintaining factors Nanog, c-Myc, and Oct4. Furthermore, Mang-NPs inhibited the components of Shh pathway and Gli targets. In vivo , Mang-NPs inhibited the progression of pancreatic intraneoplasia to pancreatic ductal adenocarcinoma and liver metastasis in KPC mice. The inhibitory effects of Mang-NPs on carcinogenesis in KPC mice were associated with downregulation of pluripotency maintaining factors (c-Myc, Nanog and Oct4), stem cell markers (CD24 and CD133), components of Shh pathway (Gli1, Gli2, Patched1/2, and Smoothened), Gli targets (Bcl-2, XIAP and Cyclin D1), and EMT markers and transcription factors (N-cadherin, Slug, Snail and Zeb1), and upregulation of E-cadherin. Overall, our data suggest that Mang-NPs can inhibit pancreatic cancer growth, development and metastasis by targeting Shh pathway.