Restoration of p53/miR-34a regulatory axis decreases survival advantage and ensures Bax-dependent apoptosis of non-small cell lung carcinoma cells.
Tumor-suppressive miR-34a, a direct target of p53, has been shown to target several molecules of cell survival pathways. Here, we show that capsaicin-induced oxidative DNA damage culminates in p53 activation to up-regulate expression of miR-34a in non-small cell lung carcinoma (NSCLC) cells. Functional analyses further indicate that restoration of miR-34a inhibits B cell lymphoma-2 (Bcl-2) protein expression to withdraw the survival advantage of these resistant NSCLC cells. In such a proapoptotic cellular milieu, where drug resistance proteins are also down-regulated, p53-transactivated Bcl-2 associated X protein (Bax) induces apoptosis via the mitochondrial death cascade. Our results suggest that p53/miR-34a regulatory axis might be critical in sensitizing drug-resistant NSCLC cells.
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Samik
S
Chakraborty
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Minakshi
M
Mazumdar
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Shravanti
S
Mukherjee
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Pushpak
P
Bhattacharjee
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Arghya
A
Adhikary
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Argha
A
Manna
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Sreeparna
S
Chakraborty
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India.
Poulami
P
Khan
Lady Brabourne College, P-1/2, Suhrawardy Ave, Kolkata, India.
Aparna
A
Sen
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, West Bengal, India. Electronic address: tanya@jcbose.ac.in.
Tanya
T
Das
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020169:Caspases; D002211:Capsaicin
Apoptosis; B cell lymphoma-2; Bcl-2 associated X protein; Capsaicin; DNA-damage; MiR-34a; Mitochondrial transmembrane potential; Reactive oxygen species; p53