Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer.

RNA polymerase mitochondria (POLRMT) is essential for mitochondrial transcription machinery and other mitochondrial functions. Its expression and potential functions in prostate cancer were explored here. The Cancer Genome Atlas prostate cancer cohort (TCGA PRAD) shows that POLRMT mRNA expression is upregulated in prostate cancer tissues and POLRMT upregulation is correlated with poor patients' survival. POLRMT mRNA and protein levels were upregulated in local prostate cancer tissues and different primary/immortalized prostate cancer cells. Genetic depletion of POLRMT, using viral shRNA or CRISPR/Cas9 gene editing methods, impaired mitochondrial functions in prostate cancer cells, leading to mitochondrial depolarization, oxidative stress, mitochondria complex I inhibition, and ATP depletion. Moreover, POLRMT depletion resulted in robust inhibition of prostate cancer cell viability, proliferation, and migration, and provoked apoptosis. Conversely, prostate cancer cell proliferation, migration, and ATP contents were strengthened following ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus impeded prostate cancer xenograft growth in nude mice. POLRMT silencing, oxidative stress, and ATP depletion were detected in POLRMT shRNA-treated prostate cancer xenograft tissues. IMT1 (inhibitor of mitochondrial transcription 1), the first-in-class POLRMT inhibitor, inhibited prostate cancer cell growth in vitro and in vivo. Together, overexpressed POLRMT is an important mitochondrial protein for prostate cancer cell growth, representing a novel and promising diagnostic and therapeutic oncotarget.

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.

Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.

miR-30c-5p Alleviated Pyroptosis During Sepsis-Induced Acute Kidney Injury via Targeting TXNIP.

Sepsis-induced acute kidney injury (SAKI) is a common complication of hospitalized patients, often leading to unacceptable mortality. Limited effective treatment or diagnosis biomarkers are available and the underlying mechanism remains unclear. The miR-30c-5p is considered as a critical mediator of kidney diseases and aberrantly decreased in patients with SAKI, while the mechanism is still unclear. For this purpose, the role of miR-30c-5p in SAKI has been investigated in this study. Here, we first confirmed that miR-30c-5p expression decreased in our septic models and was associated with the activation of NLRP3/caspase-1-mediated pyroptosis. Overexpression of miR-30c-5p alleviated the kidney injury via suppressing HK-2 cell pyroptosis. Furthermore, we identified that TXNIP was a direct target of miR-30c-5p. Upregulation of miR-30c-5p repressed the expression of TXNIP, which inhibited NLRP3, ASC, and caspase-1 expression, as well as secretion of inflammatory cytokines. In conclusion, our data suggested that miR-30c-5p negatively controlled the NLRP3 signal pathway-related pyroptosis and sepsis-induced injury via TXNIP, indicating that this axis might be a positive therapeutic target for the patient with SAKI.

MicroRNA-155-5p inhibits the invasion and migration of prostate cancer cells by targeting SPOCK1.

The aim of the present study was to determine the effect of microRNA (miR)-155-5p on the expression of testican-1 (SPOCK1) and the invasion and migration of prostate cancer cells in vitro. Bioinformatics analysis and molecular biology assays revealed that SPOCK1 may be a direct target gene of miR-155-5p. In addition, a negative correlation was identified between SPCOK1 and miR-155-5p expression in prostate tumor tissues and cell lines. miR-155-5p mimic transfection inhibited SPOCK1 expression in PC3 cells and decreased cell migration and invasion abilities, while the expression of vimentin, N-cadherin, E-cadherin, ß-catenin, matrix metalloproteinase (MMP)3 and MMP9 was upregulated. In summary, SPOCK1 was found to be a target gene of miR155-5p in prostate cancer, and miR-155-5p acts as a tumor-suppressor gene and may inhibit SPOCK1-mediated prostate cancer progression.