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HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer

Hanlin Ma1,2,3, Gonghua Qi1,2, Fang Han4

  • 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, China.

Cell Death & Disease
|March 25, 2022
PubMed

Insights

High-mobility group box 3 (HMGB3) promotes poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in ovarian cancer by interacting with PARP1. Targeting HMGB3 may help overcome this resistance, improving treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are crucial for ovarian cancer treatment, but resistance remains a significant clinical challenge.
  • High-mobility group box 3 (HMGB3) is implicated in drug resistance across various cancers, yet its role in PARPi resistance is not well-defined.

Purpose of the Study:

  • To investigate the role of High-mobility group box 3 (HMGB3) in poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSOC).
  • To elucidate the underlying molecular mechanisms by which HMGB3 influences PARPi sensitivity in ovarian cancer.

Main Methods:

  • Analysis of HMGB3 expression in HGSOC tissues and correlation with patient survival and drug resistance.
  • In vitro studies involving HMGB3 knockdown and overexpression to assess its impact on ovarian cancer cell sensitivity to PARPi.
  • Identification and characterization of the interaction between HMGB3 and PARP1 using biochemical assays.
  • Assessment of PARP1 trapping, PARylation activity, DNA damage response, and apoptosis.
  • Validation of HMGB3's role in vivo using a xenograft mouse model.

Main Results:

  • Aberrant overexpression of HMGB3 was observed in HGSOC tissues, correlating with shorter survival and increased drug resistance.
  • HMGB3 overexpression conferred resistance to PARPi, while HMGB3 knockdown sensitized ovarian cancer cells to PARPi.
  • PARP1 was identified as a novel interaction partner of HMGB3, with binding influenced by olaparib and DNA damage.
  • Loss of HMGB3 led to enhanced PARP1 trapping at DNA lesions, inhibited PARP1 activity, and promoted DNA damage response and apoptosis.
  • The role of HMGB3 in promoting PARPi resistance was confirmed in a xenograft mouse model.

Conclusions:

  • High-mobility group box 3 (HMGB3) significantly promotes poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in ovarian cancer through its interaction with PARP1.
  • Targeted inhibition of HMGB3 presents a potential therapeutic strategy to overcome PARPi resistance in ovarian cancer treatment.

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