Journal
CANCER MEDICINE
Volume 10, Issue 8, Pages 2732-2739Publisher
WILEY
DOI: 10.1002/cam4.3841
Keywords
CRISPR; Cas9; detyrosinated tubulin; ovarian cancer; paclitaxel; vasohibin‐ 2
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [19K18702, 17K11294]
- Jichi Medical University Young Investigator Award
- Grants-in-Aid for Scientific Research [17K11294, 19K18702] Funding Source: KAKEN
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VASH2 knockout in ovarian cancer cells enhances chemosensitivity to paclitaxel by reducing tubulin detyrosination and upregulating cyclin B1 expression. This study suggests that targeting VASH2 may be a promising strategy for ovarian cancer treatment by inhibiting angiogenesis and modulating microtubule activity.
Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor, and vasohibin-2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere-forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.
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