RESUMEN
Over the past decades, cancer stem cells (CSCs) have emerged as a critical subset of tumor cells associated with tumor recurrence and resistance to chemotherapy. Understanding the mechanisms underlying CSC-mediated chemoresistance is imperative for improving cancer therapy outcomes. This study delves into the regulatory role of NEIL1, a DNA glycosylase, in chemoresistance in ovarian CSCs. We first observed a decreased expression of NEIL1 in ovarian CSCs, suggesting its potential involvement in CSC regulation. Using pan-cancer analysis, we confirmed the diminished NEIL1 expression in ovarian tumors compared to normal tissues. Furthermore, NEIL1 downregulation correlated with an increase in stemness markers and enrichment of CSCs, highlighting its role in modulating CSC phenotype. Further mechanistic investigation revealed an inverse correlation between NEIL1 and RAD18 expression in ovarian CSCs. NEIL1 depletion led to heightened RAD18 expression, promoting chemoresistance possibly via enhancing Translesion DNA Synthesis (TLS)-mediated DNA lesion bypass. Moreover, dowregulation of NEIL1 results in reduced DNA damage accumulation and suppressed apoptosis in ovarian cancer. Overall, our findings unveil a novel mechanism involving NEIL1 and RAD18 in regulating chemoresistance in ovarian CSCs. Targeting this NEIL1-RAD18 axis may offer promising therapeutic strategies for combating chemoresistance and improving ovarian cancer treatment outcomes.
Asunto(s)
ADN Glicosilasas , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Células Madre Neoplásicas , Neoplasias Ováricas , Regulación hacia Arriba , Humanos , Femenino , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ADN Glicosilasas/metabolismo , ADN Glicosilasas/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Daño del ADN , Apoptosis/efectos de los fármacos , Apoptosis/genéticaRESUMEN
Ferula assa-foetida, containing organosulfides is widely used in Indian cuisine and traditionally claimed to have several medicinal properties including anticancer properties. Ferula oil enriched with organosulfides displayed significant inhibition of the cell growth in-vitro against SKOV3 and A549 cancer cells in a dose-dependent manner. This prompted us to investigate and delineate the compounds responsible for the activity. In this endeavor, the employed GC/GC-MS analysis resulted in the indecisive outcome. This led to the development of an expedient isocratic RP-HPLC method for the separation and purification of four major compounds which were further unambiguously characterised as (-)-E-2-butyl propenyl disulfide, (-)-Z-2-butyl propenyl disulfide, (-)-1-(methylthio)propyl(E)-1-propenyl disulfide, and (-)-1-(methylthio)propyl(Z)-1-propenyl disulfide employing 1H, 13C, and 2 D NMR. The isolated compounds were further evaluated for their potential against SKOV3 and A549 cell lines where a trisulfide has displayed better activity.
Asunto(s)
Ferula , Cromatografía Líquida de Alta Presión , Disulfuros , Ferula/química , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia MagnéticaRESUMEN
Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.
