Sensitizing HER2-overexpressing cancer cells to luteolin-induced apoptosis through suppressing p21(WAF1/CIP1) expression with rapamycin.
HER2 overexpression, which confers resistance to various therapeutic regimens, correlates with a poor clinical prognosis. In this study, we showed that luteolin, a naturally occurring flavonoid, is a potent stimulator of HER2 degradation. Luteolin effectively inhibited cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Furthermore, we found that low doses of luteolin up-regulated p21 expression and high doses of luteolin down-regulated its expression. Examination of the Akt/mammalian target of rapamycin (mTOR) signaling revealed that this signaling was only transiently inhibited by low doses of luteolin, which suggested that the inability to cause sustained Akt/mTOR inhibition may contribute to p21 induction and provide a survival advantage to HER2-overexpressing cancer cells. To test this hypothesis, we showed that the combined use of luteolin and mTOR inhibitor rapamycin prevented low doses of luteolin from inducing p21 expression, and HER2-overexpressing cancer cells would be sensitized toward luteolin-induced apoptosis. In addition, p21 small interfering RNA also increased the luteolin-induced cell death. In nude mice with xenografted SKOV3.ip1-induced tumors, luteolin significantly inhibited HER2 expression and tumor growth in a dose-dependent manner, and rapamycin further enhanced the effect of luteolin with a concomitant p21 inhibition. These results reveal an intriguing finding that suppressing p21 expression might have therapeutic implications and further suggest that combination of mTOR inhibitors may be a promising strategy to help increase the efficacy of preventive or therapeutic compounds against HER2-overexpressing tumors.
Chiang
Chun-Te
CT
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-ai Road, Taipei 10018, Taiwan.
Way
Tzong-Der
TD
Lin
Jen-Kun
JK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018841:HSP90 Heat-Shock Proteins; D047311:Luteolin; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse