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

Author:

Nishimura Felipe Garcia1ORCID,Sampaio Beatriz Borsani1ORCID,Komoto Tatiana Takahasi1ORCID,da Silva Wanessa Julia1ORCID,da Costa Mariana Mezencio Gregório1,Haddad Gabriela Inforçatti1,Peronni Kamila Chagas2ORCID,Evangelista Adriane Feijó3ORCID,Hossain Mohammad4ORCID,Dimmock Jonathan R.5,Bandy Brian5ORCID,Beleboni Rene Oliveira1ORCID,Marins Mozart1,Fachin Ana Lucia1ORCID

Affiliation:

1. Unidade de Biotecnologia, Universidade de Ribeirão Preto (UNAERP), Ribeirao Preto 14096-900, Brazil

2. Instituto para Pesquisa do Cancêr (IPEC), Guarapuava 85051-060, Brazil

3. Sergio Arouca National School of Public Health, Oswaldo Cruz Foundation, Manguinhos, Rio de Janeiro 21040-900, Brazil

4. School of Sciences, Indiana University Kokomo, Kokomo, IN 46904, USA

5. College of Pharmacy and Nutrition, University of Saskatchewan (USask), Saskatoon, SK S7N 5A2, Canada

Abstract

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 μM) 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.

Funder

Fundação de Amparo à Pesquisa do Estado de São Paulo

Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Publisher

MDPI AG

Reference57 articles.

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2. Understanding Breast Cancer as a Global Health Concern;Wilkinson;Br. J. Radiol.,2022

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