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LASS2 mediates Nrf2-driven progestin resistance in endometrial cancer

Bin Yang^1,2, Meiyan Hu^1,3,4, Yue Fu⁴

¹Jiangxi Medical College, Nanchang University Nanchang 330000, China.

American Journal of Translational Research

|April 12, 2021

Abstract:

Progestin administration serves as the optimal conservative treatment method for women with endometrial cancer or precancer lesions who want to preserve fertility. However, there are still at least 30% of patients in which progestin resistance occurs. LASS2 (Ceramide Synthase 2) has been reported to be involved in chemotherapy resistance, whether it also plays a role in progestin resistance is not clear. Here, we explored the detailed mechanism by which Nrf2/LASS2 contributes to progestin resistance and disease progression.

Methods:

IHC assays were performed to estimate the expression pattern of Nrf2 and LASS2. Moreover, it bears three antioxidant response elements (ARE) in the promoter region of LASS2 gene, therefore, Luciferase assays were performed to determine if Nrf2 regulates LASS2 by binding with these ARE sequence. Western Blot assays were used to determine the expression of Nrf2 and LASS2 protein among various endometrial cell lines. Relative mRNA expression levels were detected by RT-PCR. Cellular growth was monitored with CCK-8 tests. Apoptosis was determined with Annexin V-PI staining and flow cytometry analysis. siRNA knockdown was performed to investigate the effects of Nrf2 on cell proliferation.

Result:

Nrf2/LASS2 is highly expressed in endometrial cancer tissue, as compared to expression levels in normal endometrial tissue. Proliferation assays demonstrated that overexpression of Nrf2/LASS2 resulted in progestin resistance. Conversely, knockdown of LASS2 increased apoptosis and decreased cell viability. In addition, metformin overcame progestin resistance by down-regulating Nrf2/LASS2 expression.

Conclusion:

Our findings provide new insight into the mechanism of progestin resistance in type I endometrial cancer. Nrf2/LASS2 may not only be a possible marker for predicting the prognosis of endometrial cancer but also serve as a potential therapeutic target.

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) and Ceramide Synthase 2 (LASS2) drive progestin resistance in endometrial cancer. Metformin can overcome this resistance by reducing Nrf2/LASS2 expression, offering a potential therapeutic strategy.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Progestin therapy is a key fertility-sparing treatment for endometrial precancer and cancer.
Progestin resistance affects at least 30% of patients, limiting treatment efficacy.
The role of LASS2 in progestin resistance is currently unknown.

Purpose of the Study:

To investigate the mechanism of Nrf2/LASS2 in progestin resistance in endometrial cancer.
To explore the potential of targeting Nrf2/LASS2 for overcoming progestin resistance.

Main Methods:

Immunohistochemistry (IHC) and Western Blot to assess Nrf2 and LASS2 expression.
Luciferase assays to confirm Nrf2 regulation of LASS2.
RT-PCR for mRNA expression, CCK-8 for cell viability, and flow cytometry for apoptosis.
siRNA knockdown of Nrf2 and treatment with metformin.

Main Results:

Nrf2/LASS2 expression is elevated in endometrial cancer tissues compared to normal tissues.
Overexpression of Nrf2/LASS2 promotes progestin resistance and cell proliferation.
Knockdown of LASS2 enhances apoptosis and reduces cell viability.
Metformin effectively overcomes progestin resistance by downregulating Nrf2/LASS2.

Conclusions:

Nrf2/LASS2 signaling is a crucial mechanism underlying progestin resistance in type I endometrial cancer.
Nrf2/LASS2 may serve as a prognostic biomarker for endometrial cancer.
Targeting the Nrf2/LASS2 pathway presents a potential therapeutic strategy for resistant endometrial cancer.

Read full analysis

Keywords:

LASS2 Nrf2 Type I endometrial cancer progestin resistance proliferation

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