α‐Mangostin‐encapsulated PLGA nanoparticles inhibit colorectal cancer growth by inhibiting Notch pathway
Varun C. Boinpelly, Raj Kumar Verma, Sudesh Srivastav, Rakesh K. Srivastava, Sharmila Shankar
Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality. Recent studies have stated that Notch signalling is highly activated in cancer stem cells (CSCs) and plays an important role in the development and progression of CRC. Like normal colorectal epithelium, CRCs are organized hierarchically and include populations of CSCs. In order to enhance the biological activity of α-mangostin, we formulated α-mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which Mang-NPs inhibit CRC cell viability, colony formation, epithelial-mesenchymal transition (EMT) and induce apoptosis. Mang-NPs inhibited cell viability, colony formation and induced apoptosis. Mang-NPs also inhibited EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. As dysregulated signalling through the Notch receptors promotes oncogenesis, we measured the effects of Mang-NPs on Notch pathway. Mang-NPs inhibited Notch signalling by suppressing the expression of Notch receptors (Notch1 and Notch2), their ligands (Jagged 1 and DLL4), γ-secretase complex protein (Nicastrin) and downstream target (Hes-1). Notch receptor signalling regulates cell fate determination in stem cell population. Finally, Mang-NPs inhibited the self-renewal capacity of CSCs, stem cell markers (CD133, CD44, Musashi and LGR5) and pluripotency maintaining factors (Oct4, Sox-2, KLF-4, c-Myc and Nanog). Overall, our data suggest that Mang-NPs can inhibit CRC growth, EMT and CSCs' population by suppressing Notch pathway and its target. Therefore, Mang-NPs can be used for the treatment and prevention of CRC.