TY - JOUR
T1 - The molecular mechanisms of apoptosis accompanied with the epigenetic regulation of the NY-ESO-1 antigen in non-small lung cancer cells treated with decitabine (5-aza-CdR)
AU - Inchakalody, Varghese P.
AU - Hydrose, Shereena P.
AU - Krishnankutty, Roopesh
AU - Merhi, Maysaloun
AU - Therachiyil, Lubna
AU - Sasidharan Nair, Varun
AU - Elashi, Asma A.
AU - Khan, Abdul Q.
AU - Taleb, Sara
AU - Raza, Afsheen
AU - Yoosuf, Zeenath Safira K.M.
AU - Fernandes, Queenie
AU - Al-Zaidan, Lobna
AU - Mestiri, Sarra
AU - Taib, Nassiba
AU - Bedhiafi, Takwa
AU - Moustafa, Dina
AU - Assami, Laila
AU - Maalej, Karama Makni
AU - Elkord, Eyad
AU - Uddin, Shahab
AU - Al Homsi, Ussama
AU - Dermime, Said
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/4/15
Y1 - 2023/4/15
N2 - Dysregulated epigenetic modifications are common in lung cancer but have been reversed using demethylating agent like 5-Aza-CdR. 5-Aza-CdR induces/upregulates the NY-ESO-1 antigen in lung cancer. Therefore, we investigated the molecular mechanisms accompanied with the epigenetic regulation of NY-ESO-1 in 5-Aza-CdR-treated NCI–H1975 cell line. We showed significant induction of the NY-ESO-1 protein (**p < 0.0097) using Cellular ELISA. Bisulfite-sequencing demonstrated 45.6% demethylation efficiency at the NY-ESO-1 gene promoter region and RT-qPCR analysis confirmed the significant induction of NY-ESO-1 at mRNA level (128-fold increase, *p < 0.050). We then investigated the mechanism by which 5-Aza-CdR inhibits cell proliferation in the NCI–H1975 cell line. Upregulation of the death receptors TRAIL (2.04-fold *p < 0.011) and FAS (2.1-fold *p < 0.011) indicate activation of the extrinsic apoptotic pathway. The upregulation of Voltage-dependent anion-selective channel protein 1 (1.9-fold), Major vault protein (1.8-fold), Bax (1.16-fold), and Cytochrome C (1.39-fold) indicate the activation of the intrinsic pathway. We also observed the differential expression of protein Complement C3 (3.3-fold), Destrin (−5.1-fold), Vimentin (−1.7-fold), Peroxiredoxin 4 (−1.6-fold), Fascin (−1.8-fold), Heme oxygenase-2 (−0.67-fold**p < 0.0055), Hsp27 (−0.57-fold**p < 0.004), and Hsp70 (−0.39-fold **p < 0.001), indicating reduced cell growth, cell migration, and metastasis. The upregulation of 40S ribosomal protein S9 (3-fold), 40S ribosomal protein S15 (4.2-fold), 40S ribosomal protein S18 (2.5-fold), and 60S ribosomal protein L22 (4.4-fold) implied the induction of translation machinery. These results reiterate the decisive role of 5-Aza-CdR in lung cancer treatment since it induces the epigenetic regulation of NY-ESO-1 antigen, inhibits cell proliferation, increases apoptosis, and decreases invasiveness.
AB - Dysregulated epigenetic modifications are common in lung cancer but have been reversed using demethylating agent like 5-Aza-CdR. 5-Aza-CdR induces/upregulates the NY-ESO-1 antigen in lung cancer. Therefore, we investigated the molecular mechanisms accompanied with the epigenetic regulation of NY-ESO-1 in 5-Aza-CdR-treated NCI–H1975 cell line. We showed significant induction of the NY-ESO-1 protein (**p < 0.0097) using Cellular ELISA. Bisulfite-sequencing demonstrated 45.6% demethylation efficiency at the NY-ESO-1 gene promoter region and RT-qPCR analysis confirmed the significant induction of NY-ESO-1 at mRNA level (128-fold increase, *p < 0.050). We then investigated the mechanism by which 5-Aza-CdR inhibits cell proliferation in the NCI–H1975 cell line. Upregulation of the death receptors TRAIL (2.04-fold *p < 0.011) and FAS (2.1-fold *p < 0.011) indicate activation of the extrinsic apoptotic pathway. The upregulation of Voltage-dependent anion-selective channel protein 1 (1.9-fold), Major vault protein (1.8-fold), Bax (1.16-fold), and Cytochrome C (1.39-fold) indicate the activation of the intrinsic pathway. We also observed the differential expression of protein Complement C3 (3.3-fold), Destrin (−5.1-fold), Vimentin (−1.7-fold), Peroxiredoxin 4 (−1.6-fold), Fascin (−1.8-fold), Heme oxygenase-2 (−0.67-fold**p < 0.0055), Hsp27 (−0.57-fold**p < 0.004), and Hsp70 (−0.39-fold **p < 0.001), indicating reduced cell growth, cell migration, and metastasis. The upregulation of 40S ribosomal protein S9 (3-fold), 40S ribosomal protein S15 (4.2-fold), 40S ribosomal protein S18 (2.5-fold), and 60S ribosomal protein L22 (4.4-fold) implied the induction of translation machinery. These results reiterate the decisive role of 5-Aza-CdR in lung cancer treatment since it induces the epigenetic regulation of NY-ESO-1 antigen, inhibits cell proliferation, increases apoptosis, and decreases invasiveness.
KW - 5 Aza-CdR
KW - Apoptosis
KW - Epigenetic regulation
KW - Intrinsic and extrinsic apoptotic pathway
KW - Non small lung cancer
KW - NY-ESO-1
UR - https://www.scopus.com/pages/publications/85148760990
U2 - 10.1016/j.ejphar.2023.175612
DO - 10.1016/j.ejphar.2023.175612
M3 - Article
C2 - 36822455
AN - SCOPUS:85148760990
SN - 0014-2999
VL - 945
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 175612
ER -
