Metastasis and chemoresistance in CD133 expressing pancreatic cancer cells are dependent on their lipid raft integrity. (28th December 2018)

• Record Type: Journal Article
• Authors: Gupta, Vineet Kumar; Sharma, Nikita S.; Kesh, Kousik; Dauer, Patricia; Nomura, Alice; Giri, Bhuwan; Dudeja, Vikas; Banerjee, Santanu; Bhattacharya, Sanjoy; Saluja, Ashok; Banerjee, Sulagna
• Is Part Of: Cancer letters. Volume 439(2019)
• Page Start: 101
• Page End: 112
• Publication Date: 2018-12-28
• Subjects: CD133 -- Caveolin-1 -- Lipid raft -- Metastasis -- Chemoresistance; Cav Caveolin -- TIC Tumor Initiating Cells -- EMT epithelial–mesenchymal transition -- FAK Focal adhesion kinase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.09.028
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 CD133 Hi 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 CD133 Hi cells while not affecting the CD133 lo 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 TIC Hi -cells to standard chemotherapy and decrease metastasis, thereby defining a novel strategy for targeting the TIC Hi -PDAC. Highlights: CD133 associates with cholesterol and Caveolin to form lipid rafts in pancreatic TIC. Disruption of the lipid raft by targeting Cav-1 or cholesterol affects metastatic properties in TIC. Treatment with statin sensitizes CD133 Hi, resistant cancer cells to chemotherapy like paclitaxel in vitro and in vivo . These effects are exclusive to CD133 + cells. CD133 - cancer cells are not affected by the disruption of the lipid raft.