ATM/CHK/p53 Pathway Dependent Chemopreventive and Therapeutic Activity on Lung Cancer by Pterostilbene.
Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from R. undulatum and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis.
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Hani
H
Lee
Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Yonghwan
Y
Kim
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Ji Hye
JH
Jeong
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Jae-Ha
JH
Ryu
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Woo-Young
http://orcid.org/0000-0002-3706-6906
WY
Kim
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020543:Proteome / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects; D000077185:Resveratrol; D012250:Rheum / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D020543:Proteome; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C431126:rhapontigenin; C107773:pterostilbene; C041525:3,3',4,5'-tetrahydroxystilbene; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D000077185:Resveratrol