Dataset Information

Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis.

ABSTRACT: Non-surgical and safe prostate cancer (PCa) therapies are in demand. Soluble tumor necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL), a cancer-specific drug, shows preclinical efficacy but has a short circulation half-life. This research has shown that physiological fluid shear stress activates mechanosensitive ion channels (MSCs), such as Piezo1, enhancing TRAIL-mediated apoptosis in cancer cells. Herein, noninvasive, focal ultrasound (FUS) is implemented to augment the pro-apoptotic effects of TRAIL. Using thermally safe FUS parameters, it is observed that TRAIL sensitivity increases with higher FUS pressure in PCa cells, mediated by Piezo1. This is confirmed by examining the effects of calcium chelation, MSC inhibitors, and PIEZO knockdown. In vivo, a multi-dose study with 10 min FUS exposure shows that 0 and 4-h intervals between TRAIL and FUS significantly reduce tumor burden, with an increase in apoptosis evident by enhanced cleaved-caspase 3 expression. This mechanotherapy offers a clinically translatable approach by utilizing widely available FUS technology, applicable to treat additional cancer types.

SUBMITTER: Fabiano AR

PROVIDER: S-EPMC12005757 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature

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Publications

Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis.

Fabiano Abigail R AR Newman Malachy W MW Dombroski Jenna A JA Rowland Schyler J SJ Knoblauch Samantha V SV Kusunose Jiro J Gibson-Corley Katherine N KN Kaufman Benjamin G BG Ren Liqin L Caskey Charles F CF King Michael R MR

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20250220 15

Non-surgical and safe prostate cancer (PCa) therapies are in demand. Soluble tumor necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL), a cancer-specific drug, shows preclinical efficacy but has a short circulation half-life. This research has shown that physiological fluid shear stress activates mechanosensitive ion channels (MSCs), such as Piezo1, enhancing TRAIL-mediated apoptosis in cancer cells. Herein, noninvasive, focal ultrasound (FUS) is implemented to augment the pro-apop ...[more]

PMID: 39976192

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Project description:Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors. Pre-transformed BJEL cells were incubated with CMS for 0, 1, 3, 6, 8, 16 or 24 h respectively. Total RNA has been extracted from each time point and used for gene expression analysis (Affymetrix Human Gene 1.0 ST Arrays).

Dataset Information

Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis.

Publications

Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis.

Similar Datasets

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