Xiaofei Song

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.

PV-10 Induces Surface Expression of Calreticulin and HSP-70/90 in mEER cells In Vitro.

PV-10 Triggers Caspase 3/7 Activation in mEER and MTE-RAS Cells.

Molecular Mechanism of PV-10-Induced Immunogenic Cell Death through Activation of ER Stress, Autophagy, and Apoptosis Signaling.

PV-10 induces tumor regression in mEER/MTE-RAS tumors.

Primary risk factors of head and neck squamous cell carcinoma (HNSCC) include human papillomavirus infection and exposure to tobacco and excessive alcohol. Despite currently available treatments, patients with recurrent HNSCC still have poor survival, highlighting the need for innovative therapies. PV-10, also known as rose bengal sodium (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium), is a small molecule being developed as an intralesional (IL) therapeutic agent, exhibiting substantial antitumor activity across diverse cancer types, but current knowledge about the molecular mechanisms involved in response to PV-10 remains limited. We evaluated the cytotoxic effects of PV-10 in HNSCC and explored its molecular mechanisms. In vitro, we found that PV-10 induced cytotoxicity in mEER and MTE-RAS cell lines, primarily by increasing the production of reactive oxygen species and leading to apoptosis through a caspase-dependent mechanism. Additionally, we observed that PV-10 treatment increased the release of damage-associated molecular pattern molecules such as high-mobility group box 1 and ATP and enhanced expression of calreticulin, HSP-70, and HSP-90, indicating potent immunogenic cell death. In vivo, IL PV-10 injections led to significant tumor regression in both mEER and MTE-Ras models. Complete responses were observed in 7 of 21 (33%) mice in mEER, although no complete response was observed in MTE-Ras. Our data suggest that one of the possible mechanisms by which PV-10 triggers immunogenic cell death is by inducing endoplasmic reticulum stress, autophagy, and apoptosis. Our findings contribute to further understanding of the underlying mechanisms of PV-10 induced cytotoxicity and to develop future clinical trials in locally recurrent HNSCC.

PV-10 Induces Early and Late-Stage Apoptosis in a Time-Dependent Manner in MTE-Ras cells.

PV-10 Induces Tumor Regression in TC-1 Tumors in vivo.

List of Antibodies Used in the Study.

List of Reagents and Sources Used in the Study