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Updated: Apr 23, 2026
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
TRPM4 Expression as a Predictive Biomarker and a Mechanistic Driver of Acetalax Activity in Prostate Cancer:
Yuka Hoshi-Kadonosawa1, William C Reinhold2, Daiki Taniyama3
1National Cancer Institute Bethesda United States.
Abstract:
Advanced and treatment-refractory prostate cancer, including castration-resistant disease, require new therapeutic strategies. TRPM4, a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Acetalax induces oncosis-like death in TRPM4-positive triple-negative breast cancers, suggesting a TRPM4-dependent vulnerability. Here, we investigated whether TRPM4 expression defines Acetalax sensitivity in prostate cancer. We compared Acetalax sensitivity in TRPM4-high and -low prostate cancer cell lines, including androgen-dependent (LNCaP), castration-resistant (22Rv1), and androgen-independent (PC3, DU145) models. We evaluated TRPM4 dynamics and oncosis-associated phenotypes by Western blotting and immunofluorescence. Resistant clones were developed through continuous drug exposure. TRPM4 expression in patient samples was analyzed using prostate cancer tissue microarray and The Cancer Genome Atlas (TCGA). Transcriptional changes following TRPM4 loss were examined by RNA sequencing (RNA-seq). Antitumor activity and tolerability were evaluated in TRPM4-positive patient-derived xenograft (PDX) models. TRPM4-high cells (PC3, LNCaP and 22Rv1) underwent oncosis-like swelling and TRPM4 degradation upon Acetalax exposure, whereas TRPM4-low cell and resistant clones (DU145 and chronic exposure cells) remained insensitive and lacked TRPM4 expression. RNA-seq revealed transcriptomic remodeling associated with TRPM4 loss. TRPM4 was significantly elevated in tumors versus normal tissues and was unchanged across stages or Gleason scores. In TRPM4-positive PDX models, Acetalax (300 mg/kg) significantly suppressed tumor growth without body-weight loss, indicating antitumor efficacy without overt toxicity. TRPM4 is a mechanistic driver and predictive biomarker of Acetalax response in prostate cancer, supporting TRPM4-dependent targeting and providing a rationale for the clinical development of Acetalax for TRPM4-expressing and treatment-refractory prostate cancer.
Insights
Acetalax effectively targets prostate cancer by inducing cell death in TRPM4-high tumors. This study identifies TRPM4 (transient receptor potential melastatin 4) as a key biomarker for Acetalax treatment in advanced prostate cancer.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Advanced and treatment-refractory prostate cancer necessitate novel therapeutic approaches.
- Transient receptor potential melastatin 4 (TRPM4) channels are implicated in cancer progression.
- Acetalax demonstrates efficacy against TRPM4-positive triple-negative breast cancer.
Purpose of the Study:
- To investigate if TRPM4 expression predicts Acetalax sensitivity in prostate cancer.
- To evaluate Acetalax's efficacy and tolerability in TRPM4-expressing prostate cancer models.
Main Methods:
- Comparative analysis of Acetalax sensitivity in TRPM4-high and TRPM4-low prostate cancer cell lines.
- Assessment of TRPM4 dynamics and oncosis via Western blotting and immunofluorescence.
- RNA sequencing (RNA-seq) to analyze transcriptional changes post-TRPM4 loss.
- Evaluation of antitumor activity in TRPM4-positive patient-derived xenograft (PDX) models.
Main Results:
- TRPM4-high prostate cancer cells (PC3, LNCaP, 22Rv1) exhibited Acetalax-induced oncosis and TRPM4 degradation.
- TRPM4-low cells (DU145) and resistant clones were insensitive to Acetalax and lacked TRPM4 expression.
- RNA-seq revealed transcriptomic alterations linked to TRPM4 loss.
- TRPM4 was significantly elevated in prostate tumors compared to normal tissues.
- Acetalax demonstrated significant tumor suppression in TRPM4-positive PDX models without overt toxicity.
Conclusions:
- TRPM4 acts as a mechanistic driver and predictive biomarker for Acetalax response in prostate cancer.
- TRPM4-targeted therapy with Acetalax shows promise for treatment-refractory prostate cancer.
- This study provides a rationale for the clinical development of Acetalax in TRPM4-expressing prostate cancer.
