Evaluation of the High Mobility Group A1 proteins (HMGA1) as a key mediate in the anticancer activity of ‐EF24.

Abstract

The architectural chromatin binding proteins High Mobility Group A1 (HMGA1) are some of the most overexpressed proteins in malignant cancers and induce neoplastic transformation. The protein is increased as the last step of a prominent colon cancer progression pathway and mediates drug resistance, therefore correlating with a poor patient prognosis. HMGA1‐‐mediated chemoresistance results from a self‐protective process called cellular senescence. Analogs of the antioxidant, curcumin, when used in combination with traditional chemotherapeutic agents, are useful treatment options for drug resistant tumors. This study had two specific aims. The first being to investigate how colon cancer cells HCT116 respond to treatment with EF24. The second aim was to evaluate how hmga1 expression changed as a result of treatment with EF24. Our preliminary findings showed that cell viability decreased after 24‐hour treatment with low‐dose EF24, as indicated by an MTS assay, with notable discrepancies between cells that underwent a pulsed treatment regimen versus those that underwent continuous treatment. Furthermore, we demonstrated that cells exhibited fragmented DNA when treated with low‐dose EF24, which is characteristic of apoptotic cells. At higher, pulsed doses, senescence activity increased indicating the induction of a senescence pathway. Lastly, gene expression studies indicated that hmga1 was significantly down regulated in cells treated with continuous, low‐‐dose EF24. Further investigation of this pathway could lead to decreased toxicity and increased viability of combination cancer therapies.Support or Funding InformationThe research support is provided by the National Center for Research Resources (5 P20 RR16461), the National Institute of General Medical Sciences (8 P20 GM103499) from the National Institutes of Health, and the Winthrop McNair Scholars program.