Inactivation of FoxM1 transcription factor contributes to curcumin-induced inhibition of survival, angiogenesis, and chemosensitivity in acute myeloid leukemia cells
- 542 Downloads
Aberrant expression of forkhead box protein M1 (FoxM1) contributes to carcinogenesis in human cancers, including acute myeloid leukemia (AML), suggesting that the discovery of specific agents targeting FoxM1 would be extremely valuable for the treatment of AML. Curcumin, a naturally occurring phenolic compound, is suggested to possess anti-leukemic activity; however, the underlying mechanism has not been well elucidated. In this study, we found that curcumin inhibited cell survival accompanied by induction of G2/M cell cycle arrest and apoptosis in HL60, Kasumi, NB4, and KG1 cells. This was associated with concomitant attenuation of FoxM1 and its downstream genes, such as cyclin B1, cyclin-dependent kinase (CDK) 2, S-phase kinase-associated protein 2, Cdc25B, survivin, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF), as well as the reduction of the angiogenic effect of AML cells. We also found that specific downregulation of FoxM1 by siRNA prior to curcumin treatment resulted in enhanced cell survival inhibition and induction of apoptosis. Accordingly, FoxM1 siRNA increased the susceptibility of AML cells to doxorubicin-induced apoptosis. More importantly, curcumin suppressed FoxM1 expression, selectively inhibited cell survival as well as the combination of curcumin and doxorubicin exhibited a more inhibitory effect in primary CD34+ AML cells, while showing limited lethality in normal CD34+ hematopoietic progenitors. These results identify a novel role for FoxM1 in mediating the biological effects of curcumin in human AML cells. Our data provide the first evidence that curcumin together with chemotherapy or FoxM1 targeting agents may be effective strategies for the treatment of AML.
Curcumin inhibited AML cell survival and angiogenesis and induced chemosensitivity.
Aberrant expression of FoxM1 induces AML cell survival and chemoresistance.
Inactivation of FoxM1 contributes to curcumin-induced anti-leukemic effects.
Curcumin together with FoxM1 targeting agents may be effective for AML therapy.
KeywordsAcute myeloid leukemia Angiogenesis Chemosensitivity Curcumin FoxM1
This work was supported by the National Nature Science Foundation of China (81370662, 81070422, 30871088, 81070407) and the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, Ministry of Education) (20100131110060).
Conflict of interest
All the authors declared no competing interests.
- 5.Nakamura S, Hirano I, Okinaka K, Takemura T, Yokota D, Ono T, Shigeno K, Shibata K, Fujisawa S, Ohnishi K (2010) The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis 31:2012–2021PubMedCrossRefGoogle Scholar
- 6.Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T, Costa RH (2005) Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol 25:10875–10894PubMedCentralPubMedCrossRefGoogle Scholar
- 7.Ha SY, Lee CH, Chang HK, Chang S, Kwon KY, Lee EH, Roh MS, Seo B (2012) Differential expression of forkhead box M1 and its downstream cyclin-dependent kinase inhibitors p27(kip1) and p21(waf1/cip1) in the diagnosis of pulmonary neuroendocrine tumours. Histopathology 60:731–739PubMedCrossRefGoogle Scholar
- 8.Ustiyan V, Wang IC, Ren X, Zhang Y, Snyder J, Xu Y, Wert SE, Lessard JL, Kalin TV, Kalinichenko VV (2009) Forkhead box M1 transcriptional factor is required for smooth muscle cells during embryonic development of blood vessels and esophagus. Dev Biol 336:266–279PubMedCentralPubMedCrossRefGoogle Scholar
- 10.Ahmad A, Wang Z, Kong D, Ali S, Li Y, Banerjee S, Ali R, Sarkar FH (2010) FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors. Breast Cancer Res Treat 122:337–346PubMedCrossRefGoogle Scholar
- 13.Rao J, Xu DR, Zheng FM, Long ZJ, Huang SS, Wu X, Zhou WH, Huang RW, Liu Q (2011) Curcumin reduces expression of Bcl-2, leading to apoptosis in daunorubicin-insensitive CD34+ acute myeloid leukemia cell lines and primary sorted CD34+ acute myeloid leukemia cells. J Transl Med 9:71PubMedCentralPubMedCrossRefGoogle Scholar
- 16.Hartojo W, Silvers AL, Thomas DG, Seder CW, Lin L, Rao H, Wang Z, Greenson JK, Giordano TJ, Orringer MB et al (2010) Curcumin promotes apoptosis, increases chemosensitivity, and inhibits nuclear factor kappaB in esophageal adenocarcinoma. Transl Oncol 3:99–108PubMedCentralPubMedCrossRefGoogle Scholar
- 28.Wan R, Mo Y, Zhang X, Chien S, Tollerud DJ, Zhang Q (2008) Matrix metalloproteinase-2 and -9 are induced differently by metal nanoparticles in human monocytes: The role of oxidative stress and protein tyrosine kinase activation. Toxicol Appl Pharmacol 233:276–285PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Duarte VM, Han E, Veena MS, Salvado A, Suh JD, Liang LJ, Faull KF, Srivatsan ES, Wang MB (2010) Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKbeta protein of the NFkappaB pathway. Mol Cancer Ther 9:2665–2675PubMedCentralPubMedCrossRefGoogle Scholar
- 35.Prasad S, Tyagi AK, Aggarwal BB (2014) Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Can Res Treat Off J Korean Cancer Assoc 46:2–18Google Scholar