Targeting High Mobility Group Box Protein 3 to Sensitize Chemoresistant Human Ovarian Cancer Cells to Cisplatin In Vivo
Abstract
The 5-year survival rate for ovarian cancer patients in the United States is only ~48 percent. This dismal survival rate is largely due to high rates of cancer relapse, recurrence, and development of chemoresistance. Many chemotherapeutic drugs used to treat ovarian cancer induce DNA damage, and the efficient removal of such drug-induced DNA damage is one of the mechanisms that contributes to chemoresistance. We have recently demonstrated that cisplatin-resistant human ovarian cancer cells can be sensitized to cisplatin by targeting the non-histone architectural protein, High Mobility Group Box 3 (HMGB3). HMGB3, unlike its family members, HMGB1 and HMGB2, is only expressed in highly dividing cells, and is over-expressed in many ovarian tumors, such that HMGB3 may provide a selective target for cancer therapy. We have shown that the DNA damage response (DDR) kinases ATR, CHK1, and ATM are significantly down-regulated at the mRNA level, as a function of HMGB3 in human ovarian cancer cells. Further, we found that HMGB3 can localize to cisplatin-induced DNA lesions to assist in their repair, such that its depletion can significantly reduce the removal of cisplatin-DNA adducts from chemoresistant human ovarian cancer cells, leading to increased cytotoxicity and apoptosis. These results suggest that HMGB3 is a promising novel target for ovarian cancer therapy. We propose in this pilot project to assess the effects of targeting HMGB3 in vivo to sensitize chemoresistant human ovarian tumors to cisplatin treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2023
- Accession Number
- AD1228655
Entities
People
- Anirban Mukherjee
- Karen M Vasquez
Organizations
- University of Texas at Austin