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Effect of ON 01910.Na, an anticancer mitotic inhibitor, on cell-cycle progression correlates with RanGAP1

Irina A Oussenko1, James F Holland, E Premkumar Reddy

  • 1Division of Hematology and Medical Oncology, The Samuel Bronfman Department of Medicine and Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.

Cancer Research
|June 8, 2011
PubMed

Insights

The novel anticancer agent ON 01910.Na targets Ran GTPase-activating protein 1 conjugated to small ubiquitin-related modifier 1 (RanGAP1·SUMO1), inducing mitotic arrest and apoptosis without direct DNA damage. This highlights RanGAP1·SUMO1 as a potential chemotherapy target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • ON 01910.Na is a novel benzyl styryl sulfone with anticancer properties.
  • It inhibits mitotic progression and induces apoptosis in various cancer cell lines.
  • Its precise mechanism of action, particularly regarding DNA damage signaling and mitosis coordination, requires elucidation.

Purpose of the Study:

  • To investigate the effects of ON 01910.Na on DNA damage-signaling molecules (Chk1, Chk2, H2AX) and Ran GTPase-activating protein 1 conjugated to small ubiquitin-related modifier 1 (RanGAP1·SUMO1).
  • To determine if ON 01910.Na induces DNA damage or affects tubulin polymerization.
  • To identify the key molecular targets and pathways involved in ON 01910.Na's anticancer activity.

Main Methods:

  • Incubation of prostate cancer, lymphoma, and leukemic cells with ON 01910.Na for 4, 16, or 24 hours.
  • Analysis of cell lysates using SDS-PAGE and Western blotting to detect protein phosphorylation.
  • Synchronization of MOLT-3 cells to assess the temporal relationship between ON 01910.Na treatment, RanGAP1·SUMO1 phosphorylation, and mitotic arrest.

Main Results:

  • ON 01910.Na did not induce rapid phosphorylation of DNA damage-responsive molecules like Chk1, Chk2, and H2AX, unlike camptothecin and doxorubicin.
  • Significant hyperphosphorylation of RanGAP1·SUMO1 was observed within 4 hours of ON 01910.Na treatment, sustained for over 24 hours.
  • ON 01910.Na treatment led to M-phase arrest, correlating with RanGAP1·SUMO1 phosphorylation, and had minimal impact on tubulin polymerization.

Conclusions:

  • ON 01910.Na does not appear to induce DNA damage directly or act as a tubulin toxin.
  • The primary mechanism of ON 01910.Na involves sustained phosphorylation/hyperphosphorylation of RanGAP1·SUMO1, leading to M-phase arrest and apoptosis.
  • RanGAP1·SUMO1 represents a novel and promising therapeutic target pathway for cancer chemotherapy.

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