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Castration-resistance prostate cancer (CRPC), also known as hormone-refractory prostate cancer (HRPC), requires immediate attention since it is not only resistant to androgen ablation, chemo- and radiotherapy, but also highly metastatic. Increasing evidence suggests that enrichment of neuroendocrine (NE) cells is associated with CRPC. Here, combined RNA-seq and ChIP-seq analysis reveals that REST is involved in epithelial-mesenchymal transition (EMT) and stemness acquisition in NE differentiated prostate cancer (PCa) cells via direct transcriptional repression of Twist1 and CD44. Specifically we show that short-term knockdown of REST induces NE differentiation of LNCaP cells. Long-term REST knockdown enhanced the expression of Twist1 and CD44, cell migration and sphere formation. Overexpression of REST in hormone-refractory CWR22Rv1 PCa cells significantly reduces Twist1 and CD44 expression, cell migration and sphere formation. Collectively, our study uncovers REST in regulating EMT and stemness properties of NE PCa cells and suggests that REST is a potential therapeutic target for CRPC.

Gastric neoplasm is a high‐mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy‐treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4‐C/EBP homologous protein pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species‐activated general control nonderepressible 2 mediates the oligomycin‐induced ISR, and upregulates GDF15. The GDF15–glial cell‐derived neurotrophic factor family receptor a‐like–ISR–cystine/glutamate transporter‐enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15–ISR regulation might be a strategy against cisplatin resistance of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Taiwanese patients frequently experience severe hepatotoxicity associated with high‐dose methotrexate (HD‐MTX) treatment, which interferes with subsequent treatment. Drug–drug interactions occur when MTX is used in combination with proton pump inhibitors (PPIs), trimethoprim‐sulfamethoxazole (TMP‐SMX), or non‐steroidal anti‐inflammatory drugs (NSAIDs). In East Asia, real‐world analyses on the effects of co‐medication and other potential risk factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity in patients with osteogenic sarcoma (OGS) are limited. Methods: This cohort study included patients with newly diagnosed OGS who were treated with HD‐MTX between 2009 and 2017 at Taipei Veterans General Hospital. We collected data on the clinical course of HD‐MTX‐mediated acute hepatotoxicity, co‐medications, and other potential risk factors, and analyzed the effects of these factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity. Results: Almost all patients with OGS treated with HD‐MTX developed acute hepatotoxicity with elevated alanine aminotransferase (ALT) levels. Most patients with Grade 3–4 ALT elevation failed to recover to Grade 2 within 7 days. Women and children are high‐risk subgroups for HD‐MTX‐mediated elevation of ALT levels. Age is a factor that contributes to the pharmacokinetic differences of HD‐MTX. However, the concurrent use of PPIs, TMP‐SMX, or NSAIDs did not affect the elimination of MTX when administered with adequate supportive therapy. Conclusions: Co‐administration of PPIs, TMP‐SMX, or NSAIDs may have limited effects on acute hepatotoxicity in well‐monitored and adequately pre‐medicated patients with OGS undergoing chemotherapy with HD‐MTX. Clinicians should pay particular attention to ALT levels when prescribing HD‐MTX to children and women. [ABSTRACT FROM AUTHOR]