Inhibition of Hedgehog signaling induces monocytic differentiation of HL-60 cells

Abstract

There is little evidence to demonstrate the importance of the Sonic hedgehog homolog (Shh) pathway to differentiation therapy in the treatment of hematological neoplasms. Here we characterize the changes in acute myelogenous leukemia (HL-60) cells after blocking the Shh pathway by an antagonist of Smoothened, cyclopamine. Cyclopamine induces apoptosis of HL-60 cells in a dose- and time-dependent manner with increased G0/G1 cycle fraction. Treatment with cyclopamine increases the expression of monocytic cell markers CD11b and CD14, but the expression of CD13, CD33 and CD38 is unchanged. The monocytic differentiation of HL-60 cells induced by cyclopamine is also evidenced by an increase in Egr-1 expression. Importantly, cyclopamine down-regulates the phosphorylation of Akt and ERK, but activates AMP-activated protein kinase (AMPK) signaling. Further investigations should determine the clinical application of modulating the Shh pathway in the treatment of hematological malignancies.

Keywords::

• Sonic hedgehog homolog
• cyclopamine
• monocytic differentiation
• Egr-1
• Akt
• ERK

Acknowledgements

This work was supported by grants from the Taiwan Department of Health and China Medical University Hospital Cancer Research of Excellence (DOH99-TD-C-111-005), and China Medical University Hospital Research Grants (DMR-96-107, DMR-97-021, DMR-99-011). The sponsors had no role in the study design, collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript. We sincerely thank Dr. Aaron Sargeant of Charles River Laboratories for suggestions and proofreading the manuscript.

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