Molecular insights into drug-induced GDF15 regulation in cancer cells and cardiomyocytes: implications for precision medicine

A recent study published in Scientific Reports elucidated the molecular mechanisms of drug-induced regulation of growth differentiation factor 15 (GDF15).

Molecular basis of GDF15 induction and suppression by drugs in cardiomyocytes and cancer cells toward precision medicine
Study: Molecular basis of GDF15 induction and suppression by drugs in cardiomyocytes and cancer cells toward precision medicine. Image Credit: Kateryna Kon/Shutterstock.com

Introduction

GDF15 has emerged as a driver of cachexia syndrome, which often occurs in cases of drug-induced organ injury or chronic diseases like cancer. GDF15 mediates anorexia, changes in energy homeostasis or metabolism, and activation of endocrine stress responses when bound to its receptor [glial cell-derived neurotrophic factor (GDNF)-family receptor alpha-like (GFRAL)].

Studies suggest that different types of cancer cells heavily secrete GDF15 or factors inducing GDF15 expression. Drug-induced cardiotoxicity is a major concern associated with chemotherapy, with cardiomyocytes (CMs) being one of the cells overexpressing GDF15 in the presence of some cardiotoxic anti-cancer drugs.

Cachexia is described as an epiphenomenal condition with severe cancer progression. Cachexia patients are less responsive to anti-cancer treatment. Current cachexia treatment approaches primarily involve non-specific strategies such as increasing muscle mass or appetite.

Nevertheless, specific anti-GDF15 or -GFRAL antibodies have been reported. While these can directly affect GDF15, they do not address transcriptional dysregulation. 

The study and findings

In the present study, researchers explored the molecular basis of cell type- and drug-specific GDF15 regulation. They used human-induced pluripotent stem cell-derived (hiPSC)-CMs to examine how drug-induced cardiotoxicity impacts GDF15 expression. Drugs with cardiotoxic effects based on in vivo cytotoxicity to CMs were selected, leading to the identification of 20 drugs with direct cytotoxicity.

GDF15 levels measured for sub-lethal and highest drug concentrations were three-fold increased by DNA-damaging drugs [etoposide, camptothecin, amsacrine, idarubicin, and doxorubicin]. Notably, GDF15 induction by cardiotoxic and general cytotoxic drugs varied by the mode of action of drugs. Next, the team analyzed public data on gene expression in National Cancer Institute (NCI)-60 cancer cell lines treated with 15 anti-cancer drugs.

Linear regression was used to quantify responsiveness in the context of GDF15 induction. DNA-damaging drugs induced GDF15 more strongly than those with other mechanisms of action. The researchers observed four major clusters of cell lines, each containing cell lines of different tissue types. All cell lines in clusters A, B, and D were responsive to sorafenib, bortezomib, and azacytidine, respectively.

Around 64% of cluster C cell lines were doxorubicin-responsive. These clusters showed distinct characteristics differentiating them from one another. Specifically, 40.4% of cluster C cell lines contained a mutated tumor protein p53 (TP53). Two-thirds of cluster D cell lines had mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB).

Cluster A showed the lowest basal expression of GDF15, whereas cluster C had the highest. Additional analyses indicated that anti-cancer drugs differentially induced GDF15 based on the drug and cell lines' gene expression and mutational profiles.

Notably, a correlation was observed between the expression of GDF15 and bromodomain-containing protein 4 (BRD4) in half of the cell lines, suggesting that the expression of GDF15 in these cell lines was BRD4-dependent.

To further evaluate, the researchers examined gene expression data of 21 colorectal and lung cancer cell lines treated with an inhibitor of bromodomain and extraterminal (BET) proteins. They observed significantly reduced GDF15 expression in nine treated cell lines.

Notably, 19 cell lines showed increased expression of GDF11 in 19 of these cell lines. Moreover, the fold changes in GDF11 and GDF15 were inversely correlated. 

Next, several BET inhibitors were tested for their effects on drug-induced GDF15 expression in hiPSC-CMs treated with doxorubicin. Drug-treated cells exhibited up to seven-fold increased GDF15 transcript levels.

Nevertheless, BET inhibitor treatment suppressed this GDF15 overexpression. The team plotted GDF15 fold-changes against known half-maximal inhibitory concentrations (IC50s). GDF15 induction through doxorubicin decreased with higher inhibitory effects against BRD4.

Colorectal and lung cancer cell lines were stratified based on GDF11 induction and GDF15 suppression after BET inhibition. Cells with increased GDF11 and reduced GDF15 upon BET inhibition showed significantly elevated levels of p38 relative to more resistant cell lines.

Also, these were less sensitive to Akt and glycogen synthase kinase 3 (GSK3)-beta inhibitors and more dependent on BRAF. The extracellular levels of pantothenate correlated with BET inhibitor responsiveness. 

Conclusions

Taken together, the study demonstrated that the drug-induced overexpression of GDF15 in CMs was based on the drugs’ mode of action. Topoisomerase inhibitors (doxorubicin) and DNA-interacting drugs were most potent in inducing GDF15.

Nevertheless, treatment with BET inhibitors suppressed GDF15 expression induced by doxorubicin. Overall, the findings indicate that the risk of GDF15 overexpression and cachexia can be minimized through a personalized selection of anti-cancer drugs.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.

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