Exploring CDKN1A Upregulation Mechanisms: Insights into Cell Cycle Arrest Induced by NC2603 Curcumin Analog in MCF-7 Breast Cancer Cells

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Nishimura, Felipe Garcia ; Sampaio, Beatriz Borsani ; Komoto, Tatiana Takahasi ; da Silva, Wanessa Julia ; da Costa, Mariana Mezencio Gregorio ; Haddad, Gabriela Inforcatti ; Peronni, Kamila Chagas ; Evangelista, Adriane Feijo ; Hossain, Mohammad ; Dimmock, Jonathan R. ; Bandy, Brian ; Beleboni, Rene Oliveira ; Marins, Mozart ; Fachin, Ana Lucia

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 25, n. 9, p. 16-pg., 2024-05-01.

Resumo

Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide for drug development, and aiming to enhance treatment specificity and efficacy. Natural compounds, such as curcumin, offer a diverse array of chemical structures with promising therapeutic potential. Despite curcumin's benefits, challenges like poor solubility and rapid metabolism have spurred the exploration of analogs. Here, we evaluated the efficacy of the curcumin analog NC2603 to induce cell cycle arrest in MCF-7 breast cancer cells and explored its molecular mechanisms. Our findings reveal potent inhibition of cell viability (IC50 = 5.6 mu M) and greater specificity than doxorubicin toward MCF-7 vs. non-cancer HaCaT cells. Transcriptome analysis identified 12,055 modulated genes, most notably upregulation of GADD45A and downregulation of ESR1, implicating CDKN1A-mediated regulation of proliferation and cell cycle genes. We hypothesize that the curcumin analog by inducing GADD45A expression and repressing ESR1, triggers the expression of CDKN1A, which in turn downregulates the expression of many important genes of proliferation and the cell cycle. These insights advance our understanding of curcumin analogs' therapeutic potential, highlighting not just their role in treatment, but also the molecular pathways involved in their activity toward breast cancer cells. (AU)

• Processo FAPESP: 23/15218-3 - Aspectos genéticos da patogênese e estratégias de controle da candidíase de repetição e de dermatofitoses provocadas por Trichophyton rubrum
• Beneficiário: Ana Lucia Fachin Saltoratto
• Modalidade de apoio: Auxílio à Pesquisa - Regular