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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

High mobility group protein B1 is an activator of apoptotic response to antimetabolite drugs

Natalia Krynetskaia1, Hongbo Xie, Slobodan Vucetic

  • 1Temple University School of Pharmacy, 3307 North Broad Street Philadelphia, PA 19140, USA.

Molecular Pharmacology
|October 24, 2007
PubMed

Insights

High mobility group protein B1 (HMGB1) is crucial for activating cellular responses to chemotherapy drugs like 5-fluorouracil. HMGB1 deficiency increases resistance to these antimetabolites by impairing DNA damage signaling pathways.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • High mobility group protein B1 (HMGB1) is a nuclear protein involved in DNA binding and chromatin structure.
  • Anticancer drugs, including nucleoside analogs and precursors, are vital in cancer treatment.
  • Understanding cellular responses to genotoxic stress is key to improving chemotherapy efficacy.

Purpose of the Study:

  • To investigate the role of HMGB1 in the apoptotic response to widely used anticancer drugs.
  • To assess the impact of HMGB1 deficiency on cellular sensitivity to antimetabolite chemotherapy.
  • To elucidate the molecular mechanisms by which HMGB1 influences DNA damage signaling.

Main Methods:

  • Utilized a murine fibroblast model system with HMGB1-deficient (Hmgb1(-/-)) and wild-type (Hmgb1(+/+)) cells.
  • Performed chemosensitivity experiments using 5-fluorouracil, cytosine arabinoside (araC), and mercaptopurine (MP).
  • Assessed cell cycle arrest, caspase activation, p53 and H2AX phosphorylation, and proapoptotic gene promoter activity.

Main Results:

  • Hmgb1(-/-) MEFs exhibited 3 to 10-fold increased resistance to 5-FU, araC, and MP compared to Hmgb1(+/+) MEFs.
  • HMGB1 deficiency led to compromised cell cycle arrest and reduced caspase activation.
  • Reduced phosphorylation of p53 and H2AX, and diminished activation of proapoptotic genes (Bax, Puma, Noxa) were observed in Hmgb1-deficient cells.

Conclusions:

  • HMGB1 is an essential activator of the cellular response to genotoxic stress induced by chemotherapeutic antimetabolites.
  • HMGB1 acts early in antimetabolite-induced stress by promoting phosphorylation of p53 and H2AX.
  • HMGB1 represents a potential therapeutic target for modulating the activity of chemotherapeutic antimetabolites and overcoming drug resistance.

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