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Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.
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INTRODUCTION: Upper airway resistance syndrome (UARS) as obstructive sleep apnea syndrome (OSAS) has been described as abnormal breathing during sleep, based on the recording technologies and knowledge of the time. These terms have advanced the field, but are they still useful? Area Covered: Historically, the definition of UARS syndrome was aimed at recognizing pathology not covered by 'OSAS' and to prompt specialists to go further than the obvious. It aimed at pushing specialists to recognize pathologies earlier and to elicit research in the developmental features of sleep-disordered-breathing (SDB). The technology used to monitor SDB changed over-time, allowing recognition of SDB differently but not necessarily better. Expert Commentary: Currently, we have a better understanding of the development of SDB, and its evolution with aging, leading to co-morbid-OSA. However, the real issue is to recognize the problems much earlier, and to understand what can be done to prevent its development. The notions of OSA, UARS, apnea hypopnea index are only historical. There is enough knowledge to date to go beyond these definitions, to recognize problems differently and to lead to the prevention of the factors leading to SDB. The recognition of non-hypoxic sleep-disordered breathing is a step in this direction.