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Published on: January 7, 2019
Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma
Natalia Miroschnikov1, Oliver Dräger2, Dario Van Meenen1
1Institute for Anatomy II, Department of Neuroanatomy, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University of Duisburg-Essen, Medical Faculty, Duisburg, Germany.
Abstract:
The chemotherapy of retinoblastoma (RB), a malignant ocular childhood disease, is often limited by the development of resistance against commonly used drugs. We identified inositol polyphosphate 4-phosphatase type II (INPP4B) as a differentially regulated gene in etoposide-resistant RB cell lines, potentially involved in the development of RB resistances. INPP4B is controversially discussed as a tumor suppressor and an oncogenic driver in various cancers, but its role in retinoblastoma in general and chemoresistant RB in particular is yet unknown. In the study presented, we investigated the expression of INPP4B in RB cell lines and patients and analyzed the effect of INPP4B overexpression on etoposide resistant RB cell growth in vitro and in vivo. INPP4B mRNA levels were significantly downregulated in RB cells lines compared to the healthy human retina, with even lower expression levels in etoposide-resistant compared to the sensitive cell lines. Besides, a significant increase in INPP4B expression was observed in chemotherapy-treated RB tumor patient samples compared to untreated tumors. INPP4B overexpression in etoposide-resistant RB cells resulted in a significant reduction in cell viability with reduced growth, proliferation, anchorage-independent growth, and in ovo tumor formation. Caspase-3/7-mediated apoptosis was concomitantly increased, suggesting a tumor suppressive role of INPP4B in chemoresistant RB cells. No changes in AKT signaling were discernible, but p-SGK3 levels increased following INPP4B overexpression, indicating a potential regulation of SGK3 signaling in etoposide-resistant RB cells. RNAseq analysis of INPP4B overexpressing, etoposide-resistant RB cell lines revealed differentially regulated genes involved in cancer progression, mirroring observed in vitro and in vivo effects of INPP4B overexpression and strengthening INPP4B's importance for cell growth control and tumorigenicity.
Insights
Inositol polyphosphate 4-phosphatase type II (INPP4B) acts as a tumor suppressor in chemoresistant retinoblastoma (RB). Overexpressing INPP4B reduces RB cell growth and promotes apoptosis, offering a potential therapeutic target for this childhood eye cancer.
Area of Science:
- Molecular oncology
- Cancer biology
- Retinoblastoma research
Background:
- Chemotherapy resistance is a major challenge in treating retinoblastoma (RB), a childhood eye cancer.
- The role of inositol polyphosphate 4-phosphatase type II (INPP4B) in RB, particularly in chemoresistance, remains unclear.
- INPP4B has a controversial role, acting as both a tumor suppressor and oncogenic driver in various cancers.
Purpose of the Study:
- To investigate INPP4B expression in RB cell lines and patient samples.
- To analyze the functional impact of INPP4B overexpression on etoposide-resistant RB cell growth.
- To elucidate the role of INPP4B in retinoblastoma chemoresistance.
Main Methods:
- Quantitative analysis of INPP4B mRNA levels in RB cell lines and human retina.
- Assessment of INPP4B expression in chemotherapy-treated versus untreated RB patient tumors.
- In vitro and in vivo studies of INPP4B overexpression effects on RB cell viability, growth, proliferation, and tumor formation.
- Analysis of apoptosis markers (caspase-3/7) and signaling pathways (AKT, SGK3).
- RNA sequencing (RNAseq) to identify differentially regulated genes upon INPP4B overexpression.
Main Results:
- INPP4B mRNA was significantly downregulated in RB cell lines compared to healthy retina, with lower levels in etoposide-resistant cells.
- INPP4B expression increased in chemotherapy-treated RB patient tumors.
- Overexpression of INPP4B in etoposide-resistant RB cells reduced cell viability, growth, proliferation, anchorage-independent growth, and in ovo tumor formation.
- INPP4B overexpression increased caspase-3/7-mediated apoptosis and p-SGK3 levels, without affecting AKT signaling.
- RNAseq revealed differential regulation of genes involved in cancer progression upon INPP4B overexpression.
Conclusions:
- INPP4B exhibits a tumor-suppressive role in chemoresistant retinoblastoma.
- INPP4B overexpression inhibits RB cell growth and tumorigenicity, potentially through apoptosis induction and SGK3 signaling.
- INPP4B represents a promising therapeutic target for overcoming etoposide resistance in retinoblastoma.
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