TL;DR
It is demonstrated that NAC1 may be a critical factor in the development of chemoresistance, offering a potential novel target for the treatment of CRC.
: Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, largely due to the emergence of resistance to standard chemotherapeutic regimens. The identification of molecular determinants of chemoresistance is therefore critical to improve patient stratification and therapeutic efficacy. Here, we investigate the functional role of Pinin (PNN), a multifunctional protein involved in RNA processing and gene regulation, in mediating chemoresistance in CRC. Methods: SW620 and HCT-116 colorectal cancer cells were used to investigate the functional role of PNN. Pnn expression was silenced by siRNA and lentiviral shRNA approaches. Cell sensitivity to 5-fluorouracil and oxaliplatin was evaluated by MTT assay, while apoptosis was assessed by Annexin V/7-AAD flow cytometry. Migration, invasion, and clonogenic capacity were analyzed using wound-healing, modified Boyden chamber
PON2 appears to sustain chemoresistance by affecting important mechanisms related to ROS detoxification, glucose metabolism, and anti-apoptotic signaling by affecting important mechanisms related to ROS detoxification, glucose metabolism, and anti-apoptotic signaling.
Gastric cancer remains a leading cause of cancer-related mortality worldwide, largely due to resistance to platinum-based chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in tumor progression and immune evasion; however, its cell-intrinsic role in chemoresistance remains incompletely understood. This study demonstrates that IDO1 functions as a critical regulator of cisplatin sensitivity in gastric cancer cells through a ROS-mediated mechanism. IDO1 expression was suppressed using siRNA in two gastric cancer cell lines, AGS and MKN45, followed by cisplatin treatment. Cell viability, oxidative stress levels, apoptosis-related gene expression, and caspase-3/7 activity were assessed to evaluate the functional consequences of IDO1 knockdown. IDO1 silencing significantly enhanced cisplatin-induced cytotoxicity in both cell lines, accompanied by increased intracellular reactive oxygen species (ROS) levels and a marked transcriptional shift toward a pro-apoptotic gene expression profile characterized by upregulation of Bax and p53 and downregulation of anti-apoptotic Bcl-2. Critically, functional apoptosis analysis revealed that combined IDO1 silencing and cisplatin treatment markedly increased caspase-3/7 activity, confirming activation of the execution phase of apoptosis. These findings establish that IDO1 limits apoptotic susceptibility in a cell-intrinsic manner and contributes to cisplatin sensitivity in gastric cancer cells. The mechanistic basis involves IDO1’s ROS-scavenging function: by suppressing IDO1, cells lose their capacity to neutralize ROS, leading to excessive ROS accumulation that triggers mitochondrial dysfunction and activates p53-dependent apoptotic pathways. In conclusion, this study identifies IDO1 as a key regulator of oxidative stress-associated, caspase-dependent apoptosis in gastric cancer and suggests that targeting IDO1 in combination with platinum-based chemotherapy represents a promising strategy to enhance the efficacy of gastric cancer treatment. These findings provide a rationale for clinical translation and provide a foundation for future preclinical and clinical studies.
BACKGROUND Extrachromosomal DNA (ecDNA), as a dynamic genetic vector, enables tumor cells to exhibit enhanced adaptability under chemotherapeutic stress. However, its functional role in tumor malignancy and the development of drug resistance in gastric cancer (GC) remains unclear. OBJECTIVE This study aims to investigate the relationship between chemotherapy and ecDNA in GC, and explore its potential as a novel therapeutic target. METHODS We first analyzed our clinical data to reveal associations between ecDNA induction by chemotherapy and metastatic progression. Then we investigated the role of ecDNA in mediating chemoresistance and malignant phenotypes in cisplatin-resistant cell models using WGS, SEM, western blot, qPCR, flow cytometry, and immunofluorescence. RESULTS We found that neoadjuvant chemotherapy (NAC) promoted ecDNA formation from linear amplicons, which was associated with increased tumor mutational burden, poorer survival, and higher distant metastasis risk. The generation of ecDNA in GC was more likely to originate from chromosomes 5, 7, 8, 9, and 12. In cisplatin-resistant models, ecDNA emergence promoted various malignant phenotypes, including DNA damage repair, G1 arrest, autophagy, proliferation, migration, and invasion, which were attenuated by ecDNA inhibition. EcDNA inhibitors delayed acquired resistance in wild-type cells and showed combinatorial activity with cisplatin in resistant GC, supporting clinical potential. CONCLUSION Our study revealed that cisplatin could promote ecDNA generation, which enhanced malignant phenotypes, including cell proliferation, motility and drug resistance, and was associated with poorer patient prognosis. Targeting ecDNA with inhibitors could reverse these effects, supporting further preclinical evaluation.
The study demonstrates that TFEB regulates the expression of the multidrug efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2), a crucial factor in drug resistance mechanisms, and targets TNKS represents a potentially effective therapeutic approach to address cisplatin resistance and improve treatment outcomes in TNBC.
