Targeting the ERK1/2 and p38 MAPK Pathways Attenuates Golgin-97 Depletion-Induced Cancer Progression in Breast Cancer

Immunology Life Sciences Cell Biology Oncology Medicine
Golgi apparatus Golgin-97 breast cancer MAPK signaling metastasis inflammatory cytokine

Targeting ERK1/2 and p38 MAPK Pathways Attenuates Golgin-97 Depletion-Induced Breast Cancer Progression

Research Background

Breast cancer is the most common type of cancer among women worldwide, with triple-negative breast cancer (TNBC) having a particularly high metastasis rate and poor prognosis. TNBC lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, rendering endocrine therapy ineffective and making chemotherapy the primary treatment option. However, drug resistance and side effects (such as pneumonia and severe inflammation) limit the efficacy of chemotherapy. Therefore, identifying new molecular targets and treatment strategies is crucial for improving the prognosis of TNBC patients.

The Golgi apparatus is an important organelle within cells, responsible for the transport and modification of proteins and lipids. Recent studies have shown that the Golgi apparatus plays a significant role in cancer cell migration and invasion. Golgin-97, a protein located in the trans-Golgi network (TGN), is involved in regulating Golgi integrity and vesicular trafficking. Previous research has indicated that low expression of Golgin-97 is associated with poor prognosis in breast cancer patients, but the specific mechanisms underlying its role in cancer progression remain unclear.

Research Source

This study was conducted by Yu-Chin Liu and her team from Chang Gung University and published in 2025 in the journal Cell Communication and Signaling. The research team systematically investigated the role of Golgin-97 in breast cancer progression and its regulatory mechanisms using gene knockout (CRISPR-Cas9), animal models (zebrafish and mouse xenografts), multi-omics analysis (next-generation sequencing and proteomics), and kinase inhibitor treatments.

Research Process and Results

1. Establishment and Validation of Golgin-97 Knockout Models

The research team first constructed a Golgin-97 knockout (KO) MDA-MB-231 breast cancer cell line using CRISPR-Cas9 technology. The absence of Golgin-97 protein was confirmed by Western blotting, and it was observed that the expression levels of IκBα and TGN46 proteins decreased in KO cells, while cell migration and invasion capabilities significantly increased.

2. Animal Models Validate the Impact of Golgin-97 Depletion on Cancer Metastasis

To validate the role of Golgin-97 depletion in vivo, the research team used zebrafish and mouse models. In the zebrafish model, Golgin-97 KO cells exhibited a higher metastasis rate, particularly on the second day post-injection, with a significantly higher rate compared to the control group. In the mouse xenograft model, Golgin-97 KO cells showed a significant increase in the number of lung metastatic foci and tumor cell density, indicating that Golgin-97 depletion promotes breast cancer metastasis and invasion.

3. Multi-Omics Analysis Reveals the Regulatory Network of Golgin-97 Depletion

Through next-generation sequencing (NGS) and quantitative proteomics analysis, the research team found that Golgin-97 depletion led to the significant upregulation of 783 genes, involving key regulatory networks such as the Wnt signaling pathway, MAPK kinase cascades, and inflammatory cytokines. Ingenuity Pathway Analysis (IPA) further revealed the important roles of upstream regulators such as IL-1β, TNF, and BMP4 in Golgin-97 depletion-induced cancer progression.

4. Targeting ERK1/2 and p38 MAPK Pathways to Inhibit Cancer Progression

The research team discovered that Golgin-97 depletion promotes breast cancer cell migration and invasion by activating the ERK1/2 and p38 MAPK signaling pathways. By using the ERK1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580, the team successfully inhibited the migration ability of Golgin-97 KO cells and reduced the expression of inflammatory mediators such as IL-1β, IL-6, and MMP1. Additionally, the combined use of these two inhibitors significantly enhanced the efficacy of the chemotherapy drug paclitaxel (PTX), reducing lung metastasis and lung injury.

5. Mechanism of Golgin-97 Downregulation Under Hypoxic Conditions

The study also found that hypoxia is a physiological condition leading to the downregulation of Golgin-97 expression. By treating cells with the hypoxia mimetic CoCl2, the research team observed the accumulation of HIF1α protein and a decrease in the protein levels of Golgin-97, TGN46, and IκBα. Meanwhile, the ERK1/2 and p38 MAPK signaling pathways were activated, indicating that Golgin-97 expression is negatively regulated by the MAPK signaling pathway under hypoxic conditions.

Research Conclusions and Significance

1. The Tumor-Suppressive Role of Golgin-97 in Breast Cancer

The study demonstrates that Golgin-97 inhibits breast cancer cell migration and invasion by regulating the ERK1/2 and p38 MAPK signaling pathways. Depletion of Golgin-97 leads to the activation of inflammatory factors and the Wnt/MAPK signaling pathway, thereby promoting cancer progression.

2. Therapeutic Potential of Targeting MAPK Signaling Pathways

ERK1/2 and p38 MAPK inhibitors not only inhibit cancer progression induced by Golgin-97 depletion but also enhance the efficacy of chemotherapy drugs, reducing lung metastasis and lung injury. This provides new treatment strategies for TNBC patients.

3. Regulation of Golgin-97 Expression Under Hypoxia

The study reveals the mechanism of Golgin-97 downregulation under hypoxic conditions and proposes a negative feedback loop between the ERK/MAPK signaling pathway and Golgin-97. This discovery offers new insights into the regulation of Golgi function in the tumor microenvironment.

Research Highlights

  1. Innovative Research Methods: The study combines CRISPR-Cas9 gene editing, multi-omics analysis, and animal models to systematically reveal the regulatory mechanisms of Golgin-97 in breast cancer.
  2. Breakthrough in Treatment Strategies: For the first time, the study proposes a treatment regimen combining ERK1/2 and p38 MAPK inhibitors with chemotherapy drugs, significantly improving the efficacy of TNBC treatment.
  3. Link Between Hypoxia and Cancer Progression: The study uncovers the mechanism of Golgin-97 downregulation under hypoxic conditions, providing a new direction for research on the tumor microenvironment.

Research Value

This study not only elucidates the tumor-suppressive role of Golgin-97 in breast cancer and its regulatory mechanisms but also provides new targets and strategies for TNBC treatment. By targeting the ERK1/2 and p38 MAPK signaling pathways, the research team successfully inhibited cancer progression and metastasis while reducing the side effects of chemotherapy drugs. This achievement offers important theoretical foundations and practical guidance for future cancer drug development and clinical treatment.