ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells

Sep 21, 2026

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ACA-28 is investigated as an ERK MAPK pathway modulator with anticancer activity in melanoma and pancreatic cancer cells. Global gene expression analysis of SK-MEL-28 cells identified Nrf2 as a major upregulated pathway after ACA-28 treatment. ACA-28 elevates reactive oxygen species (ROS) and increases Nrf2 protein, consistent with reduced proteasomal repression under oxidative stress. ROS scavenging with N-acetyl cysteine and Nrf2 knockdown diminish the response, while Nrf2 overexpression confers resistance. ML385 strengthens ACA-28-mediated cell death in pancreatic cancer models.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

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Introduction

ERK MAPK signaling in cancer

Rationale for ROS-inducing anticancer therapy

ACA-28 discovery and mechanistic background

Hindawi Oxidative Medicine and Cellular Longevity Volume 2024, Article ID 7683793, 12 pages [https://doi.org/10.1155/2024/7683793](https://doi.org/10.1155/2024/7683793) Research Article ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells Teruaki Takasaki, 1 Yasuyuki Hamabe, 1 Kenta Touchi, 1 Golam Iftakhar Khandakar, 1 Takeshi Ueda,2,3 Hitoshi Okada,2,3 Kazuko Sakai,4 Kazuto Nishio,4 Genzoh Tanabe,5 and Reiko Sugiura 1,3 1Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan 2Department of Biochemistry, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan 3Anti-Aging Center, Kindai University, Osaka 577-8502, Japan 4Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan 5Laboratory of Organic Chemistry, Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan Correspondence should be addressed to Reiko Sugiura; [sugiurar@phar.kindai.ac.jp](sugiurar@phar.kindai.ac.jp) Received 5 October 2023; Revised 19 February 2024; Accepted 27 February 2024; Published 11 March 2024 Academic Editor: Giselle Cerchiaro Copyright © 2024 Teruaki Takasaki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identiﬁed an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identiﬁed nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine signiﬁcantly attenuated the anticancer activity of ACA-28 . Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28 . Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1 . Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28 . 1. Introduction The RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) MAPK pathway is a highly conserved signal transduction system that is frequently dysregulated in a large number of human cancers as a result of genetic alterations in their components or upstream activation of cell-surface receptors [1–4]. Aberrant activation of this pathway contributes to tumorigenesis and tumor development [5]. Consequently, tremendous efforts have been dedicated

FAQs

What anticancer effect is reported for ACA-28?

ACA-28 shows anticancer activity that involves inducing cell death in melanoma and pancreatic cancer cells, with evidence linking the effect to ROS generation.

How does ACA-28 influence Nrf2 signaling?

ACA-28 upregulates Nrf2 signaling, increasing Nrf2 protein levels in melanoma cells, consistent with activation under oxidative stress.

Why do Nrf2 levels affect sensitivity to ACA-28?

Cells with higher basal Nrf2 or transient Nrf2 overexpression are more resistant to ACA-28, whereas Nrf2 knockdown promotes greater sensitivity and cell death.

Sep 21, 2026

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