Open AccessHMGA 2 as a functional antagonist of PARP 1 inhibitors in tumor cells
Author(s) -
HombachKlonisch Sabine,
Kalantari Forouh,
Medapati Manoj Reddy,
Natarajan Suchitra,
Krishnan Sai Nivedita,
KumarKanojia Aditya,
Thanasupawat Thatchawan,
Begum Farhana,
Xu Fred Y.,
Hatch Grant M.,
Los Marek,
Klonisch Thomas
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12390
Subject(s) - olaparib , parp1 , poly adp ribose polymerase , dna damage , cancer research , parp inhibitor , dna repair , biology , hmga2 , microbiology and biotechnology , chemistry , polymerase , biochemistry , dna , gene , microrna
Poly(ADP‐ribose) polymerase 1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP 1 inhibitors. Expression of HMGA 2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA 2 and PARP 1 in DNA damage‐induced PARP 1 activity. We used human triple‐negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA 2 colocalizes and interacts with PARP 1. High cellular HMGA 2 levels correlated with increased DNA damage‐induced PARP 1 activity, which was dependent on functional DNA ‐binding AT ‐hook domains of HMGA 2. HMGA 2 inhibited PARP 1 trapping to DNA and counteracted the cytotoxic effect of PARP inhibitors. Consequently, HMGA 2 decreased caspase 3/7 induction and increased cell survival upon treatment with the alkylating methyl methanesulfonate alone or in combination with the PARP inhibitor AZD 2281 (olaparib). HMGA 2 increased mitochondrial oxygen consumption rate and spare respiratory capacity and increased NAMPT levels, suggesting metabolic support for enhanced PARP 1 activity upon DNA damage. Our data showed that expression of HMGA 2 in cancer cells reduces sensitivity to PARP inhibitors and suggests that targeting HMGA 2 in combination with PARP inhibition may be a promising new therapeutic approach.