@Article{or.2026.084313,
AUTHOR = {Molli Alice, Buonvicino Daniela, Mattei Gianluca, Bonacchi Leonardo, Scuffi Irene, Calcagno Sara, Isoldi Giulia, Schiavone Nicola, De Logu Francesco, Magi Alberto, Lulli Matteo, Parenti Astrid, Lapucci Andrea},
TITLE = {Pinin Modulation Restores Chemosensitivity in SW620 and HCT-116 Colon Cancer Cells},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/28074},
ISSN = {1555-3906},
ABSTRACT = {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. <i>Pnn</i> 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, and colony formation assays. Metabolic reprogramming following <i>Pnn</i> depletion was characterized using Seahorse extracellular flux analysis. Transcriptomic alterations were investigated by Nanopore RNA sequencing, followed by differential gene expression, bioinformatic, and gene set enrichment analyses. Results: <i>Pnn</i> silencing significantly enhanced sensitivity to 5-fluorouracil and oxaliplatin in SW620 cells, as demonstrated by reduced cell viability, decreased IC<sub>50</sub> values, and increased apoptotic responses. Transcriptomic profiling revealed extensive gene expression reprogramming, affecting pathways related to cell cycle progression, DNA damage response, and stress signaling. To corroborate these findings, <i>Pnn</i>-silenced HCT-116 cells were used to confirm the observed cytotoxic effects and independently validate selected differentially expressed genes identified by RNA-seq in SW620 cells. Notably, <i>Pnn</i> depletion induced a marked impairment of mitochondrial oxidative phosphorylation without compensatory glycolytic activation, indicating reduced metabolic flexibility under stress conditions. Functionally, <i>Pnn</i> silencing also decreased clonogenic capacity and invasive behavior. Conclusion: Collectively, these findings identify <i>Pnn</i> as a key regulator of chemoresistance and reveal its involvement in transcriptional control, metabolic adaptation, and stress response. Targeting PNN-related pathways may represent a promising therapeutic strategy to restore chemosensitivity and improve outcomes in colorectal cancer, although further validation is required.},
DOI = {10.32604/or.2026.084313}
}