Metastasis and chemoresistance in CD133 expressing pancreatic cancer cells are dependent on their lipid raft integrity

Cancer Lett. 2018 Dec 28:439:101-112. doi: 10.1016/j.canlet.2018.09.028. Epub 2018 Oct 2.


Metabolic rewiring is an integral part of tumor growth. Among metabolic pathways, the Mevalonic-Acid-Pathway (MVAP) plays a key role in maintaining membrane architecture through cholesterol synthesis, thereby affecting invasiveness. In the current study, we show for the first time that CD133Hi pancreatic tumor initiating cells (TIC) have increased expression of MVAP enzymes, cholesterol-content and Caveolin expression. Further, we show that CD133 in these cells is localized in the lipid-rafts (characterized by Cav-1-cholesterol association). Disruption of lipid-rafts by either depleting Cav-1 or by inhibiting MVAP by lovastatin decreased metastatic-potential and chemoresistance in CD133Hi cells while not affecting the CD133lo cells. Additionally, disruption of lipid-raft results in deregulation of FAK-signaling, decreasing invasiveness in pancreatic-TICs. Furthermore, this also inhibits ABC-transporter activity resulting in sensitizing TICs to standard chemotherapeutic agents. Repurposing existing drugs for new clinical applications is one of the safest and least resource intensive approaches to improve therapeutic options. In this context, our study is extremely timely as it shows that targeting lipid-rafts with statins can sensitize the normally resistant pancreatic TICHi-cells to standard chemotherapy and decrease metastasis, thereby defining a novel strategy for targeting the TICHi-PDAC.

Keywords: CD133; Caveolin-1; Chemoresistance; Lipid raft; Metastasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AC133 Antigen / genetics*
  • AC133 Antigen / metabolism
  • Animals
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Cell Line, Tumor
  • Cholesterol / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Lovastatin / pharmacology
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism*
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Paclitaxel / pharmacology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Xenograft Model Antitumor Assays / methods


  • AC133 Antigen
  • Caveolin 1
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • PROM1 protein, human
  • Cholesterol
  • Lovastatin
  • Paclitaxel