Targeting Cancer Stem Cells with a Novel Glycolytic Inhibitor to Overcome Metastasis and Chemoresistance in Small Cell Lung Cancer
Abstract
Based preliminary data and additional data generated by this project, we have determined that the glycolytic inhibitor PFK158 reduced cell viability, attenuated glucose uptake, lactate production and ATP levels in several SCLC cell lines (H1408, H1882 and H1876.Consistent with this, KD of PFKFB3, the target of PFK158 also inhibited glycolysis in these cell lines. While PFK 158 treatment induced apoptotic mediated cell death, it was independent of autophagy. Overall, our results show for the first time that synergy with QC and carboplatin involves a complex interplay between AV and apoptosis in OVCa cells and is associated with upregulation of INP2, downregulation of p62, and simultaneous upregulation of CTSL only in resistant cells. While PFK158 treatment resulted in the downregulation of several cancer stem markers such as CD!33, SOX2 and STAT3, it was independent of PFKFB3. More importantly, our FACS analysis of cancer stem cell enriched spheroid cultures positive for ALDH and CD133 of H1048 and 1882 was effectively targeted by PFK158. Additional results also showed that PFK158 sensitized SCLC cell lines to CBPt mediated cytotoxicity. Collectively, these results show that PFK158 treatment in addition to inhibiting the glycolytic rate also significantly reduced the cancer stem cell population to induce apoptotic cell death of SCLC cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1133100
Entities
People
- Vijayalakshmi Shridhar
Organizations
- Mayo Clinic