Inhibition of Plasminogen Activator Inhibitor-1 (PAI-1) by Tiplaxtinin Attenuates the Aggressive Phenotype of Vulvar Squamous Cell Carcinoma Cells In Vitro

Sep 22, 2026

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Vulvar squamous cell carcinoma (VSCC) is rare yet clinically burdensome, motivating targeted therapies. Plasminogen activator inhibitor-1 (PAI-1) is a central regulator of the plasminogen activation system and is often overexpressed in cancers, correlating with poor outcomes. This study evaluates whether tiplaxtinin, a specific PAI-1 inhibitor, can suppress aggressive VSCC cell behavior in vitro. PAI-1 inhibition reduces viability, proliferation, migration, and invasion of A431 and Cal-39 cells without a significant induction of apoptosis.

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Materials and Methods

doi: 10.21873/invivo.14345 Inhibition of Plasminogen Activator Inhibitor-1 (PAI-1) by Tiplaxtinin Attenuates the Aggressive Phenotype of Vulvar Squamous Cell Carcinoma Cells In Vitro JAQUELINE WARMBOLD, JULIA GALLWAS and CARSTEN GRÜNDKER University Medical Center Göttingen, Department of Gynecology and Obstetrics, Göttingen, Germany Abstract Background/Aim: Vulvar squamous cell carcinoma (VSCC), while relatively rare, is associated with significant morbidity. Activation of G-protein coupled estrogen receptor 1 (GPER1), which has a tumor-suppressing effect in VSCC, leads to reduced expression of plasminogen activator inhibitor-1 (PAI-1). PAI-1, a key regulator of the plasminogen activation system, is overexpressed in various cancers and is linked to poor prognosis. Its role and potential as a therapeutic target in VSCC remain poorly explored. This study investigated the effects of the specific PAI-1 inhibitor tiplaxtinin (PAI-039, TPX) on the aggressive behavior of VSCC cells in vitro. Materials and Methods: Expression of PAI-1 was verified by western blot. The effects of TPX treatment on viability, proliferation, migration, and invasion of A431 and Cal-39 VSCC cells were assessed using AlamarBlue, crystal violet, gap closure, and Boyden chamber assays, respectively. Apoptosis was examined using the Annexin V/propidium iodide (PI) assay. Results: Both VSCC cell lines showed PAI-1 expression. With increasing TPX concentrations, viability and proliferation of the VSCC cells decreased significantly. Cell migration and invasion were both significantly reduced under treatment with the PAI-1 inhibitor. Apoptosis was not significantly induced by TPX. Conclusion: PAI-1 inhibitor TPX showed a strong inhibitory effect on VSCC cells, significantly reducing their viability, proliferation, migration and invasive capacity. This compound showed a strong ability to suppress important cell functions associated with cancer progression, making it a promising candidate for VSCC therapy to specifically inhibit growth and spread of VSCC. Keywords: Vulvar squamous cell carcinoma (VSCC), G-protein-coupled estrogen receptor 1 (GPER1), plasminogen activator inhibitor-1 (PAI-1), tiplaxtinin. ✉ Carsten Gründker, Department of Gynecology and Obstetrics, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. Tel: +49 (0)5513969810, [e-mail: grundker@med.uni-goettingen.de](e-mail: grundker@med.uni-goettingen.de) Received February 13, 2026 | Revised March 24, 2026 | Accepted April 16, 2026 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ©2026 The Author(s) . Published by the International Institute of Anticancer Research. Introduction Tumors ofthe vulva (VC) can originate from different cell types. Vulvarsquamous cell carcinoma (VSCC) is the most common type, accounting for 90% of cases. VSCCs develop from intraepithelial neoplasia of the vulva, which can arise with or without infection with HPV types 16 and 18 (1, 2) . VC initially metastasizes lymphogenically, particularly to the inguinal lymph nodes. As the disease progresses, pelvic lymph nodes may also be affected. Hematogenous metastases are rare. The most important prognostic marker is therefore the status of the inguinal lymph nodes (3) . The relative 5-year survival rate in Germany or the USA is currently around 70%(4, 5) . G-protein-coupled estrogen receptor 1 (GPER1) plays a critical role in progression, migration, and therapy resistance of various tumor entities (6) . However, the overall picture remains inconsistent. GPER1 also appears to be involved in tumor suppression. Current research provides a range of answers to the question of whether GPER1 is tumor-promoting or tumor-suppressive. In VSCC, GPER1 seems to play a tumor-suppressive role (7, 8) . In addition, activation of GPER1

FAQs

What is the rationale for targeting PAI-1 in vulvar squamous cell carcinoma?

PAI-1 is overexpressed in multiple cancers and is linked to poor prognosis. In VSCC, PAI-1’s role is insufficiently defined, motivating evaluation of PAI-1 as a therapeutic target.

How was PAI-1 expression and the effect of tiplaxtinin assessed in VSCC cells?

PAI-1 expression was verified by western blot. Tiplaxtinin effects on viability, proliferation, migration, and invasion were measured using AlamarBlue, crystal violet, gap closure, and Boyden chamber assays, and apoptosis was evaluated using an Annexin V/propidium iodide assay.

What were the main findings regarding tiplaxtinin’s impact on VSCC aggressiveness?

Tiplaxtinin reduced viability and proliferation and significantly decreased migration and invasion in A431 and Cal-39 cells. Apoptosis was not significantly induced by tiplaxtinin.

Sep 22, 2026

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