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Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation

Abstract

Cabozantinib is a potent tyrosine kinase inhibitor with multiple targets including MET, VEGFR2, RET, KIT, and FLT3. Cabozantinib is widely used for the treatment of medullary thyroid cancer and renal cell carcinoma. We recently suggested cabozantinib as a potential therapeutic alternative for acute myeloid leukemia (AML) patients with FLT3-internal tandem duplication (FLT3-ITD). Here, we report that cabozantinib can promote differentiation in erythroid leukemia cells. We found that K562 erythroid leukemia cells treated with 1 μM cabozantinib for 72 h underwent erythroid lineage differentiation. Transcriptomic analysis revealed that various pathways associated with heme biosynthesis, hemoglobin production, and GATA1 targets were upregulated, whereas cell survival pathways were downregulated. Further examination revealed that cabozantinib-induced erythroid differentiation is at least in part regulated by JNK activation and phosphorylation. Levels of phosphorylated BCR-ABL, AKT, STAT5, ERK, and p38 also decreased following cabozantinib treatment. Therefore, we indicate that cabozantinib has dual functions. First, it induces K562 cell differentiation toward the erythroid lineage by upregulating heme biosynthesis, globin synthesis, and erythroid-associated reactions. Second, cabozantinib inhibits K562 cell proliferation by inhibiting the phosphorylation of BCR-ABL and the downstream MAPK, PI3K-AKT, and JAK-STAT signaling pathways.

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Fig. 1: Cabozantinib inhibited K562 cell proliferation and induced differentiation toward erythroid lineage.
Fig. 2: Signaling pathways alternations after cabozantinib treatment.
Fig. 3: The involvement of JNK pathway in cabozantinib-induced differentiation.
Fig. 4: The effect of cabozantinib on cell cycle and associated molecules.

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Acknowledgements

This study was supported by research grants from Taiwan Health Foundation, The National Taiwan University Hospital (NTUH106-003417), the Ministry of Health and Welfare (MOHW109-TDU-B-211-134009), and the Ministry of Science and Technology (MOST105-2320-B-002-051-MY3 and MOST108-2320-B-002-050-MY3), Taiwan.

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Correspondence to Hsiung-Fei Chien or Liang-In Lin.

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Fu, YH., Ou, DL., Yang, YR. et al. Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation. Cancer Gene Ther (2021). https://doi.org/10.1038/s41417-021-00358-w

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