CBP-mediated FOXO-1 Acetylation Inhibits Pancreatic Tumor Growth by Targeting SirT

Overview

Journal Mol Cancer Ther

Date 2014 Jan 15

PMID 24419059

Citations 36

Authors

Kartick C Pramanik

Neel M Fofaria

Parul Gupta

Sanjay K Srivastava

Affiliations

Soon will be listed here.

Abstract

Here, we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated c-jun-NH2-kinase (JNK); forkhead box transcription factor, class O (FOXO1); and BIM in BxPC-3, AsPC-1, and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3 and PARP, indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, capsaicin treatment caused a steady increase in the nuclear expression of FOXO-1, leading to increased DNA binding. Capsaicin-mediated expression of BIM was found to be directly dependent on the acetylation of FOXO-1. The expression of CREB-binding protein (CBP) was increased, whereas SirT-1 was reduced by capsaicin treatment. Using acetylation mimic or defective mutants, our result demonstrated that phosphorylation of FOXO-1 was mediated through acetylation by capsaicin treatment. JNK inhibitor attenuated the phosphorylation of FOXO-1, activation of BIM, and abrogated capsaicin-induced apoptosis. Moreover, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis, whereas overexpression of FOXO-1 augmented its effects. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP, indicating the role of BIM in apoptosis. Oral administration of 5 mg/kg capsaicin substantially suppressed the growth of BxPC-3 tumor xenografts in athymic nude mice. Tumors from capsaicin-treated mice showed an increase in the phosphorylation of JNK, FOXO-1, BIM, and levels of CBP, cleavage of caspase-3, PARP, and decreased SirT-1 expression. Taken together, our results suggest that capsaicin activated JNK and FOXO-1, leading to the acetylation of FOXO-1 through CBP and SirT-1. Acetylated FOXO1 induced apoptosis in pancreatic cancer cells through BIM activation.

Citing Articles

Apoptotic vesicles derived from bone marrow mesenchymal stem cells increase angiogenesis in a hind limb ischemia model via the NAMPT/SIRT1/FOXO1 axis.

Chen J, Shen Z, Chen B, Liu S, Mei Y, Li K Stem Cell Res Ther. 2025; 16(1):105.

PMID: 40025506 PMC: 11872336. DOI: 10.1186/s13287-025-04245-1.

The role of acetylation and deacetylation in cancer metabolism.

Wang C, Ma X Clin Transl Med. 2025; 15(1):e70145.

PMID: 39778006 PMC: 11706801. DOI: 10.1002/ctm2.70145.

Forkhead box O proteins: steering the course of stem cell fate.

Cheng M, Nie Y, Song M, Chen F, Yu Y Cell Regen. 2024; 13(1):7.

PMID: 38466341 PMC: 10928065. DOI: 10.1186/s13619-024-00190-1.

FoxO1 promotes ovarian cancer by increasing transcription and METTL14-mediated mA modification of SMC4.

Tan L, Wang S, Huang S, Tie Y, Sai N, Mao Y Cancer Sci. 2024; 115(4):1224-1240.

PMID: 38403332 PMC: 11006996. DOI: 10.1111/cas.16120.

Acetylation of FOXO1 activates Bim expression involved in CVB3 induced cardiomyocyte apoptosis.

Hu Y, Yi L, Yang Y, Wu Z, Kong M, Kang Z Apoptosis. 2023; 29(7-8):1271-1287.

PMID: 38127284 PMC: 11263423. DOI: 10.1007/s10495-023-01924-3.

References

YUN T . Update from Asia. Asian studies on cancer chemoprevention. Ann N Y Acad Sci. 2000; 889:157-92. DOI: 10.1111/j.1749-6632.1999.tb08734.x. View

van der Horst A, Tertoolen L, de Vries-Smits L, Frye R, Medema R, Burgering B . FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279(28):28873-9. DOI: 10.1074/jbc.M401138200. View

Glauser D, Schlegel W . The emerging role of FOXO transcription factors in pancreatic beta cells. J Endocrinol. 2007; 193(2):195-207. DOI: 10.1677/JOE-06-0191. View

Sahu R, Srivastava S . The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst. 2009; 101(3):176-93. PMC: 2724856. DOI: 10.1093/jnci/djn470. View

Huang H, Tindall D . Dynamic FoxO transcription factors. J Cell Sci. 2007; 120(Pt 15):2479-87. DOI: 10.1242/jcs.001222. View

Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A . Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci U S A. 2005; 102(32):11278-83. PMC: 1183558. DOI: 10.1073/pnas.0502738102. View

Cai B, Chang S, Becker E, Bonni A, Xia Z . p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem. 2006; 281(35):25215-22. DOI: 10.1074/jbc.M512627200. View

Monsereenusorn Y . Subchronic toxicity studies of capsaicin and capsicum in rats. Res Commun Chem Pathol Pharmacol. 1983; 41(1):95-110. View

Yang Y, Hou H, Haller E, Nicosia S, Bai W . Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 2005; 24(5):1021-32. PMC: 554122. DOI: 10.1038/sj.emboj.7600570. View

10.

Zhang R, Humphreys I, Sahu R, Shi Y, Srivastava S . In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis. 2008; 13(12):1465-78. DOI: 10.1007/s10495-008-0278-6. View

11.

Urbich C, Knau A, Fichtlscherer S, Walter D, Bruhl T, Potente M . FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J. 2005; 19(8):974-6. DOI: 10.1096/fj.04-2727fje. View

12.

Barreyro F, Kobayashi S, Bronk S, Werneburg N, Malhi H, Gores G . Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J Biol Chem. 2007; 282(37):27141-27154. DOI: 10.1074/jbc.M704391200. View

13.

Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M . Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004; 101(27):10042-7. PMC: 454161. DOI: 10.1073/pnas.0400593101. View

14.

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View

15.

Lopez-Carrillo L, Avila M, Dubrow R . Chili pepper consumption and gastric cancer in Mexico: a case-control study. Am J Epidemiol. 1994; 139(3):263-71. DOI: 10.1093/oxfordjournals.aje.a116993. View

16.

Putcha G, Le S, Frank S, Besirli C, Clark K, Chu B . JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron. 2003; 38(6):899-914. DOI: 10.1016/s0896-6273(03)00355-6. View

17.

Inoue S, Riley J, Gant T, Dyer M, Cohen G . Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia. 2007; 21(8):1773-82. DOI: 10.1038/sj.leu.2404760. View

18.

Fu Z, Tindall D . FOXOs, cancer and regulation of apoptosis. Oncogene. 2008; 27(16):2312-9. PMC: 2819403. DOI: 10.1038/onc.2008.24. View

19.

Pramanik K, Srivastava S . Apoptosis signal-regulating kinase 1-thioredoxin complex dissociation by capsaicin causes pancreatic tumor growth suppression by inducing apoptosis. Antioxid Redox Signal. 2012; 17(10):1417-32. PMC: 3437051. DOI: 10.1089/ars.2011.4369. View

20.

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View