Objective:

This study investigated the role of particularly-interesting-new-cysteine-histidine-rich protein-1 (PINCH1) in glioblastoma multiforme (GBM) progression and recurrence, as well as PINCH’s potential as a therapeutic target. The study focuses on understanding how changes in PINCH1 protein expression and post-translational modifications (PTM) impact cell cycle dynamics and cell survival upon chemotherapeutic agent exposure. Understanding PINCH1’s role in GBM development/progression may lead to improved treatment approaches.

Background:

Gliomas represent 80% of brain cancers, with glioblastoma multiforme (GBM) being the most common and aggressive type. Despite treatment, most low-grade astrocytomas progress to GBM, which has a nearly 100% recurrence rate within 9 months and a median survival of 15 months. GBM's invasiveness and resistance to therapy contribute to its poor prognosis.

Design/Methods:

Glioblastoma cell lines (U87, LN229, U251) and normal human primary astrocytes (HPA) were cultured in vitro under hypoxic and low-glucose conditions to mimic some aspects of the tumor microenvironment. PINCH1 expression was increased and decreased, and amino acids were mutated to regulate PTM in GBM cells lines and HPA. Cells were exposed to temozolomide (TMZ) and analyzed via immunolabeling with PINCH1, and glial fibrillary acidic protein (GFAP) antibodies followed by confocal microscopy. Flow cytometry assessed apoptosis and cell cycle changes in response to PINCH1 modulation under various stress conditions. 

Results:

Preliminary findings indicated increased PINCH1 expression in cells subjected to stressors. GBM cells showed less cell death in the presence of stressors or TMZ.  Of clinical relevance, PINCH1 overexpression decreased TMZ-induced apoptosis in GBM. 

Conclusions:

Future studies will investigate how regulating PINCH1 increases GBM cell vulnerability to chemotherapy. We will explore the role of PINCH1 SUMOylation, a PTM that modulates chemotherapeutic resistance. We aim to assess the clinical feasibility of regulating PINCH1 as a strategy to enhance GBM cell sensitivity to treatment, prevent astrocytoma progression to GBM, and reduce recurrence rates.