AMPK Activation of Apoptotic Markers in Human Breast Cancer Cell Lines with Different p53 Backgrounds: MCF-7, MDA-MB-231 and T47D Cells

Abstract

Background: Downregulation of AMPK has been established as a major contributor to carcinogenesis in many types of human cancer. We sought to investigate the influence of activated AMPK on apoptotic markers in human breast cancer cells differing in their p53 status, as well as estrogen receptor status (MCF-7 (p53+ and ER+), MDA-MB-231 (p53 mutant and ER-) and T47D (p53 mutant and ER+)). Methods: We examined the effect of AICAR-activated AMPK on PARP cleavage, Bax redistribution, the involvement of intrinsic and extrinsic pathways of apoptosis using selective caspase inhibitors and cell cycle progression and p21 levels. Results: PARP cleavage occurred to a greater extent in MCF-7 and MDA-MB-231 cells, whereas Bax translocation was slower in MDA-MB-231 cells. Although there were quantitative differences in the effect of caspase inhibitors, it was clear that AMPK activation predominately affected the intrinsic pathway of apoptosis. Although, p21 was increased in all 3 cell types, there were quantitative and time differences. Apoptosis, as measured by fluorimetry, was increased in all three cell types. Conclusion: The impact of AMPK activation was cell type dependent resulting in differential activation of apoptotic markers, confirming that the genetic background of breast cancer may have an influence on the mode of action of AMPK. Thus, different anti-tumour mechanisms may be elicited depending on the cellular genotype.

Troglitazone-Induced PRODH/POX-Dependent Apoptosis Occurs in the Absence of Estradiol or ERβ in ER-Negative Breast Cancer Cells

“…Therefore, further studies on antiestrogen therapy accompanied by TGZ treatment should be undertaken as an approach to experimental therapy of ER negative breast cancer cells. Downregulation of AMPK, metabolic regulator involved in control of cell growth and survival has been established as a major contributor to carcinogenesis in many types of human cancer [51]. We have found that TGZ induced in dose-dependent manner AMPK expression.…”

“…Although the mechanism is not well understood, the activation of p53 in the cells cultured in estradiol-free medium is supported by some other authors, suggesting that estradiol inactivates P53 [54] or estrogen receptor prevents p53-dependent apoptosis in breast cancer [55,56]. It seems that in the absence of estradiol, TGZ-treated MCF-7 cells may undergo apoptosis by p53 signaling [50,51], while MDA-MB-231 cells, due to p53 mutation, through PRODH/POXdependent ROS generation.…”

“…Interestingly, a pro-apoptotic effect of AMPK in cancer cells and a mutual relationship between AMPK and p53 have been reported. It cannot be excluded that pro-apoptotic effect of TGZ involves cross-talk between AMPK and p53 [51]. Although the mechanism is not well understood, the activation of p53 in the cells cultured in estradiol-free medium is supported by some other authors, suggesting that estradiol inactivates P53 [54] or estrogen receptor prevents p53-dependent apoptosis in breast cancer [55,56].…”

3,3'-Diindolylmethane induces gastric cancer cells death via STIM1 mediated store-operated calcium entry

“…AMPK, a crucial cellular energy sensor regulating metabolic processes 39 , has been reported as a novel tumor suppressor in various cancers 40 . Moreover, the activation of p-AMPK was associated with ER stress, which led to cells death 43 .…”

“…Moreover, the activation of p-AMPK was associated with ER stress, which led to cells death 43 . Studies have shown that metformin can enhance the anti-cancer effect of dasatinib mainly through p-AMPK mediated ER stress 40 . Consecutively, in our study, whether p-AMPK/p-ACC involved in regulating anti-cancer by DIM-mediated ER stress is added.…”