Role of SMAD signaling in drug-induced apoptosis in colon cancer
DOI:
https://doi.org/10.3329/bjp.v9i4.20418Keywords:
Chemotherapy, Colon cancer, SMADAbstract
Aberrations in SMAD signaling have been widely associated with colon cancer progression. However, their significance in modulating drug response remains unknown. In this study we investigated the response of chemotherapeutic drugs in colon cancer cells that are with (SW620 and SW480) and without aberrations (FET-1 and Caco2) in SMAD signaling. These results showed that curcumin, 5-fluorouracil and their combinations induced less cell death in SMAD signaling non-responsive cells, while the apoptosis was (>2 fold) higher in SMAD responsive cells. Furthermore, these results showed that the apoptosis in SMAD non-responsive cells was reversed and increased (~2-fold) upon ectopic expression of SMAD-4. Finally, correlation with patients undergoing chemotherapy for colon cancer showed a strong association between SMAD aberration and tumor relapse in chemotherapy. Overall, the present data showed that SMAD signaling modulates the drug responses and their signaling status should be considered while designing chemotherapy regimen for colon cancer patients.
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Abdollah S, Macias-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wran JL. TBRI phosphorylation of SMAD2 on Ser465 and Ser467 is required for SMAD2-SMAD4 complex formation and signaling. J Biol Chem. 1997; 272: 27678-85.
Chacko BM, Qin B, Correia JJ, Lam SS, de Caestecker MP, Lin K. The L3 loop and C-terminal phosphorylation jointly define SMAD proteintrimerization. Nat Struct Biol. 2001; 8: 248-53.
Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K. Structural basis of heteromeric SMAD protein assembly in TGF-b signaling. Mol Cell. 2004; 15: 813-23.
Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M, Day F, Li S, Tsui C, Lipton L, Desai J, Jones IT, McLaughlin S, Ward RL, Hawkins NJ,
Ruszkiewicz AR, Moore J, Zhu HJ, Mariadason JM, Burgess AW, Busam D, Zhao Q, Strausberg RL, Gibbs P, Sieber OM. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 2013; 73: 725-35.
Frederick JP, Wang XF Smads "freeze" when they ski. Structure 2002; 10: 1607-11.
Grau AM, Datta PK, Zi J, Halder SK, Beauchamp RD. Role of Smad proteins in the regulation of NF-kappaB by TGF-beta in colon cancer cells. Cell Signal. 2006; 18: 1041-50.
Hossain DM, Bhattacharyya S, Das T, Sa G. Curcumin: The multi-targeted therapy for cancer regression. Front Biosci (Schol Ed). 2012; 4: 335-55.
Labianca R, Beretta GD, Kildani B, Milesi L, Merlin F, Mosconi S, Pessi MA, Prochilo T, Quadri A, Gatta G, de Braud F, Wils J. Colon cancer. Crit Rev Oncol Hematol. 2010; 74: 106-33.
Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemotherapeutic drug response. Biosci Rep. 2012; 32: 361-74.
Massague J. TGFb in cancer. Cell 2008; 134: 215-30.
Miyazono K, ten Dijke P, Heldin CH. TGF-beta signaling by Smad proteins. Adv Immunol. 2000; 75: 115-57.
Pasetto LM, D'Andrea MR, Jirillo A, Rossi E, Monfardini S. Stable disease in advanced colorectal cancer: Therapeutic implications. Anti-cancer Res. 2006; 26: 511-22.
Sang HQ, Gu JF, Yuan JR, Zhang MH, Jia XB, Feng L. The protective effect of smilax glabra extract on advanced glycation end products-induced endothelial dysfunction in HUVECs via RAGE-ERK1/2-NF-κB pathway. J Ethnopharmacol. 2014; 155: 785-95.
Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, ten Dijke P, Heldin CH. Phosphorylation of Ser465 and Ser467 in the Cterminus of SMAD2 mediates interaction with SMAD4 and is required for transforming growth factor-beta signaling. J Biol Chem. 1997; 272: 28107-15.
Shi Y, Hata A, Lo RS, Massague J, Pavletich NP. A structural basis formutational inactivation of the tumour suppressor SMAD4. Nature 1997; 388: 87-93.
Zhang L, Zhou F, ten Dijke P. Signaling interplay between transforming growth factor-β receptor and PI3K/AKT pathways in cancer. Trends Biochem Sci. 2013; 38: 612-20.
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