Estrogen is known to play a causative role in the development of sporadic breast cancers and chemoresistance. However, studies on the mechanism and proteins involved in mediating the oncogenic effects of estrogen are very limited. Recently, Aurora-A, a centrosomal protein kinase, which induces centrosome amplification and genomic instability, has been shown to be upregulated during long-term treatment of rats with estrogen and was implicated in estrogen-induced oncogenesis. Herein, we present results of the studies carried out in short-term in vitro cultures to understand the regulation of Aurora-A by estrogen and the effect of downregulation of Aurora-A on estrogen-induced breast tumorigenesis and chemoresistance. Treatment of breast cancer cells with 10 nM 17β-estradiol (E2) resulted in the upregulation of Aurora-A levels in an estrogen receptor-dependent manner. However, the upregulation by E2 was not restricted to Aurora-A alone. Following release from the tamoxifen-induced arrest, the appearance of Aurora-A in the presence of estradiol in MCF7 cells coincided with the appearance of other mitotic markers suggesting that the spike in Aurora-A levels is an indirect consequence of estrogen-mediated cell proliferation. Thus, at least in short-term in vitro studies, Aurora-A is not a specific direct target of estrogen. However, downregulation of Aurora-A by RNA interference led to a significant decrease in estrogen-induced, anchorage-dependent, and independent growth of MCF7 cells. Moreover, knockdown of Aurora-A could overcome estrogen-induced decrease in docetaxel sensitivity of MCF7 cells. Cumulatively, we propose that the upregulation of Aurora-A by estrogen in short-term in vitro cultures is an indirect consequence of estrogen-induced cell proliferation. Nevertheless, Aurora-A inhibitors could be exploited to override the effects of estrogen on breast tumorigenesis and chemoresistance.
Heng Hong Lee, Yansong Zhu, Karthik M Govindasamy and Ganesan Gopalan
Xiaqing Xu, Meimei Si, Honggang Lou, Youyou Yan, Yunxi Liu, Hong Zhu, Xiaoe Lou, Jian Ma, Difeng Zhu, Honghai Wu, Bo Yang, Haoshu Wu, Ling Ding and Qiaojun He
Accumulating clinical evidence indicates that diabetic liver cancer patients are less sensitive to intra-arterial chemotherapy than non-diabetic cancer patients. However, the underlying mechanism remains largely uncharacterized. Here, we report that hyperglycemia inhibits AMPK pathway and subsequently reduces adriamycin (ADR)-induced DNA damage, resulting in decreased chemotherapeutic sensitivity of ADR. HepG2 and Bel-7402 cells were treated with ADR in various glucose conditions and then subjected to cell proliferation assay and apoptosis. The IC50 of ADR greatly increased with the increasing concentration of glucose (15 ± 4 nM to 93 ± 39 nM in HepG2, 78 ± 8 nM to 1310 ± 155 nM in Bel-7402). Both FACs and Western blot analysis indicated that high concentration of glucose protected cells from ADR-induced apoptosis. Mouse hepatoma H22 xenografts were established both in db/db diabetic mice and STZ-induced diabetic mice. The inhibitory effect in tumor growth of ADR was significantly reduced in diabetic mice, which could be recovered by insulin therapy. Hyperglycemia greatly ameliorated AMPK activation and H2AX expression caused by ADR treatment. Pretreatment with compound C or AMPK silencing eliminated hyperglycemia reduced cytotoxicity of ADR. However, the impaired cytotoxicity in hyperglycemia was recovered by treatment with AMPK activator AICAR. This study indicates that hyperglycemia impairs the chemotherapeutic sensitivity of ADR by downregulating AMPK pathway and reducing ADR-induced DNA damage.