scholarly journals IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells

2018 ◽  
Vol 19 (11) ◽  
pp. 3561 ◽  
Author(s):  
Leah Persaud ◽  
Jason Mighty ◽  
Xuelin Zhong ◽  
Ashleigh Francis ◽  
Marifer Mendez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Protein Kinase ◽  
Er Stress ◽  
Cancer Cell ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Breast Cancer Cell Lines ◽  
Extrinsic Pathway ◽  
Eif2α Phosphorylation

Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24.

scholarly journals AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture

2019 ◽  
Author(s):  
Dongqing Zheng ◽  
Jonathan H. Sussman ◽  
Matthew P. Jeon ◽  
Sydney T. Parrish ◽  
Alireza Delfarah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Oxygen Species

ABSTRACTOncogenes can generate metabolic vulnerabilities in cancer cells. Here, we tested how AKT and MYC affect the ability of cells to shift between respiration and glycolysis. Using immortalized mammary epithelial cells, we discovered that constitutively active AKT but not MYC induced cell death in galactose culture, where cells must rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were short-lived, and AKT-expressing cells recommenced growth after ~15 days in galactose. To identify the mechanisms regulating AKT-mediated cell death, we used metabolomics and found that AKT cells dying in galactose upregulated glutathione metabolism. Next, using proteomics, we discovered that AKT-expressing cells dying in galactose upregulated nonsense-mediated mRNA decay, a marker of sensitivity to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered that galactose induced ROS in cells expressing AKT but not MYC. Additionally, ROS were required for the galactose-induced death of AKT-expressing cells. We then tested whether these findings could be replicated in breast cancer cell lines with constitutively active AKT signaling. Indeed, we found that galactose induced rapid cell death in breast cancer cell lines and that ROS were required for galactose-induced cell death. Together, our results demonstrate that AKT but not MYC induces a metabolic vulnerability in cancer cells, namely the restricted flexibility to use oxidative phosphorylation.ImplicationsThe discovery that AKT but not MYC restricts the ability to utilize oxidative phosphorylation highlights that therapeutics targeting tumor metabolism must be tailored to the individual genetic profile of tumors.

γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death

2015 ◽  
Vol 93 (4) ◽  
pp. 306-320 ◽  
Author(s):  
Roshan V. Tiwari ◽  
Parash Parajuli ◽  
Paul W. Sylvester
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cell ◽  
Human Breast Cancer ◽  
Beclin 1 ◽  
Time Dependent ◽  
Human Breast ◽  
Cancer Cell Death

The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.

Vitamin K2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines

Breast Cancer ◽  
2019 ◽  
Vol 27 (2) ◽  
pp. 225-235
Author(s):  
Shinsuke Miyazawa ◽  
Shota Moriya ◽  
Hiroko Kokuba ◽  
Hirotsugu Hino ◽  
Naoharu Takano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Apoptotic Cell ◽  
Cancer Cell Lines ◽  
Vitamin K2 ◽  
Breast Cancer Cell Lines ◽  
Autophagosome Formation
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