Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer

IRE1α is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1α cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1α cleaves select mRNAs through regulated IRE1α-dependent decay (RIDD). Accumulating evidence implicates IRE1α in the regulation of lipid metabolism. However, the roles of XBP1s and RIDD in this process remain ill-defined. In this study, transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α reveals changes in lipid metabolism genes associated with accumulation of triacylglycerols (TAGs). We identify DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Inhibition of IRE1α, leads to DGAT2-dependent accumulation of TAGs in lipid droplets and sensitizes cells to nutritional stress, which is rescued by treatment with the DGAT2 inhibitor PF-06424439. Our results highlight the importance of IRE1α RIDD activity in reprograming cellular lipid metabolism.

 

Comments:

The given passage describes a study focused on the role of IRE1α, a protein involved in the unfolded protein response (UPR), in cancer progression and lipid metabolism. Here's a breakdown of the key findings and implications of the study:

1. IRE1α activity in cancer: The passage states that IRE1α is constitutively active in several cancers and contributes to cancer progression. This suggests that the dysregulation of IRE1α signaling may play a role in promoting tumor growth.

2. XBP1s production: When activated, IRE1α cleaves XBP1 mRNA, leading to the production of a transcription factor called XBP1s. However, the exact role of XBP1s in lipid metabolism regulation remains unclear in this context.

3. Regulated IRE1α-dependent decay (RIDD): In addition to XBP1 mRNA, IRE1α can cleave select mRNAs through a process called RIDD. This study identifies DGAT2 mRNA, which encodes an enzyme involved in triacylglycerol (TAG) biosynthesis, as a target of RIDD.

4. Changes in lipid metabolism genes: Pharmacological inhibition of IRE1α in triple-negative breast cancer cells leads to changes in lipid metabolism genes. Specifically, the study finds an accumulation of TAGs, which are stored in lipid droplets.

5. DGAT2 and TAG accumulation: The study links the inhibition of IRE1α to the accumulation of TAGs in lipid droplets through DGAT2, the rate-limiting enzyme in TAG biosynthesis. Inhibition of IRE1α results in DGAT2-dependent TAG accumulation.

6. Sensitization to nutritional stress: Inhibition of IRE1α leads to increased sensitivity of cancer cells to nutritional stress. This effect is rescued by treatment with a DGAT2 inhibitor called PF-06424439, suggesting that DGAT2-dependent TAG accumulation is associated with cellular response to nutrient availability.

7. Reprogramming lipid metabolism: The findings of this study suggest that the RIDD activity of IRE1α plays a crucial role in reprogramming cellular lipid metabolism. Inhibition of IRE1α leads to changes in lipid metabolism gene expression, accumulation of TAGs, and increased sensitivity to nutritional stress.

In summary, this study demonstrates the involvement of IRE1α in regulating lipid metabolism in triple-negative breast cancer cells. The inhibition of IRE1α leads to changes in lipid metabolism gene expression, accumulation of TAGs through the regulation of DGAT2, and increased sensitivity to nutritional stress. These findings provide insights into the potential therapeutic targeting of IRE1α and DGAT2 in cancer treatment and highlight the importance of IRE1α's role in reprogramming cellular lipid metabolism.

Related Products

Cat.No.	Product Name	Information
S9921	PF-06424439	PF-06424439 is a first orally bioavailable small-molecule inhibitor of DGAT2 with an IC50 of 14 nM.

Related Targets

Acyltransferase