Secretory pathway Ca2+-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry

Makena, Monish R.; Ko, Myungjun; Mekile, Allatah X.; Senoo, Nanami; Dang, Donna K.; Warrington, John M.; Buckhaults, Phillip; Talbot, C. Conover; Claypool, Steven M.; Rao, Rajini

doi:10.1016/j.redox.2022.102240

Cited by 10 publications

(10 citation statements)

References 55 publications

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“…Apoptosis is closely related to DNA damage [ 20 , 21 ]. When DNA damage occurs in tumour cells, the DNA damage response system of the cell is rapidly activated to repair the damaged DNA [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Marine-Derived Stichloroside C2 Inhibits Epithelial–Mesenchymal Transition and Induces Apoptosis through the Mitogen-Activated Protein Kinase Signalling Pathway in Triple-Negative Breast Cancer Cells

Cui

Ding

Liu

et al. 2022

Journal of Oncology

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Background. Triterpenoid saponins from sea cucumbers exhibit significant antitumour, antifungal, and antibacterial activities. However, the associated molecular mechanisms have yet to be elucidated. In this study, we screened and explored the antitumour activity and underlying mechanisms of triterpenoid saponins isolated from Thelenota ananas. Methods. We isolated and purified sea cucumber saponins, determined their chemical structures, and confirmed their function in vitro. We also screened and explored the antitumour activity and underlying mechanisms of triterpenoid saponins isolated from Thelenota ananas. Results. Four saponins were discovered from sea cucumber Thelenota ananas collected from the South China Sea. We found that stichloroside C2 (STC2) inhibited the proliferation and clonogenesis of the human triple-negative breast cancer (TNBC) cell line MDA-MB-231 and mouse TNBC cell line 4 T1 in a dose-dependent manner and induced apoptosis and cycle arrest in these two TNBC cell lines. STC2 induced DNA damage in two TNBC cell lines and significantly increased the protein expression level of the DNA double-strand break marker γ-H2AX. STC2 downregulated the protein expression levels of phosphorylated cyclin-dependent kinase 1 (CDK1), cyclin B1, CDK2, and cyclin A2 in MDA-MB-231 and 4 T1 cells. STC2 upregulated Bax and cleaved PARP protein expression in two types of breast cancer cells. In addition, STC2 promoted E-cadherin expression; inhibited vimentin expression; upregulated the phosphorylation levels of the mitogen-activated protein kinase (MAPK) signalling pathway-related proteins p38, JNK, and ERK1/2; and downregulated Akt phosphorylation. Conclusions. STC2 exerts anti-TNBC activity, inhibits epithelial–mesenchymal transition (EMT), and induces apoptosis by regulating the cell cycle, EMT-related proteins, and MAPK signalling pathway.

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Section: Resultsmentioning

confidence: 99%

Marine-Derived Stichloroside C2 Inhibits Epithelial–Mesenchymal Transition and Induces Apoptosis through the Mitogen-Activated Protein Kinase Signalling Pathway in Triple-Negative Breast Cancer Cells

Cui

Ding

Liu

et al. 2022

Journal of Oncology

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“…Furthermore, SPCA1 and SPCA2 overexpression in the GA is associated with a pro-survival role in breast cancer [ 71 - 73 ] . Knocking down SPCA1 [ 73 ] and SPCA2 [ 72 ] has shown to reduce MDA-MB-231 [ 73 ] and MCF-7 [ 72 ] breast cancer cells proliferation, respectively.…”

Section: Targeting Ca 2+ Signalling Proteins Invol...mentioning

confidence: 99%

Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

Kumari,

Pullaguri,

Rath

et al. 2024

Cancer Drug Resist

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Globally, cancer, as a major public health concern, poses a severe threat to people’s well-being. Advanced and specialized therapies can now cure the majority of people with early-stage cancer. However, emerging resistance to traditional and novel chemotherapeutic drugs remains a serious issue in clinical medicine. Chemoresistance often leads to cancer recurrence, metastasis, and increased mortality, accounting for 90% of chemotherapy failures. Thus, it is important to understand the molecular mechanisms of chemoresistance and find novel therapeutic approaches for cancer treatment. Among the several factors responsible for chemoresistance, calcium (Ca2+) dysregulation plays a significant role in cancer progression and chemoresistance. Therefore, targeting this derailed Ca2+ signalling for cancer therapy has become an emerging research area. Of note, the Ca2+ signal and its proteins are a multifaceted and potent tool by which cells achieve specific outcomes. Depending on cell survival needs, Ca2+ is either upregulated or downregulated in both chemosensitive and chemoresistant cancer cells. Consequently, the appropriate treatment should be selected based on Ca2+ signalling dysregulation. This review discusses the role of Ca2+ in cancer cells and the targeting of Ca2+ channels, pumps, and exchangers. Furthermore, we have emphasised the role of Ca2+ in chemoresistance and therapeutic strategies. In conclusion, targeting Ca2+ signalling is a multifaceted process. Methods such as site-specific drug delivery, target-based drug-designing, and targeting two or more Ca2+ proteins simultaneously may be explored; however, further clinical studies are essential to validate Ca2+ blockers’ anti-cancer efficacy.

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“…Concrete mechanisms of kidney cell damage in the pathological process of AKI could include the following: (1) Intracellular Ca 2+ overload: During renal ischemia and hypoxia, the initial decrease in ATP causes depolarization of the cell membrane and activates the intracellular Na + −Ca 2+ exchange mechanism, which results in a massive extracellular Ca 2+ influx through the Ca 2+ channel. 10,11 (2) Oxidative stress injury: ATP is extensively degraded to hypoxanthine during renal ischemia and hypoxia, and hypoxanthine can further react with increased oxygen molecules during reperfusion, fueling the generation of massive amounts of reactive oxygen species (ROS). 12,13 Excessive ROS can not only damage organelle and plasma membranes, accelerating Ca 2+ influx via transmembrane ion transport perturbations, but also severely damage the structural functions of mitochondria and the endoplasmic reticulum (ER).…”

Section: Introductionmentioning

confidence: 99%

“…In I/R-induced AKI, a pathophysiological cascade is triggered, including intracellular calcium ion ([Ca 2+ ] i ) overload, oxidative stress, cellular energy metabolism disorder, and inflammatory response activation, in which the relationship among these mechanisms is intimately interwoven and plays pivotal roles in the pathological progression of AKI. Concrete mechanisms of kidney cell damage in the pathological process of AKI could include the following: (1) Intracellular Ca 2+ overload: During renal ischemia and hypoxia, the initial decrease in ATP causes depolarization of the cell membrane and activates the intracellular Na + –Ca 2+ exchange mechanism, which results in a massive extracellular Ca 2+ influx through the Ca 2+ channel. , (2) Oxidative stress injury: ATP is extensively degraded to hypoxanthine during renal ischemia and hypoxia, and hypoxanthine can further react with increased oxygen molecules during reperfusion, fueling the generation of massive amounts of reactive oxygen species (ROS). , Excessive ROS can not only damage organelle and plasma membranes, accelerating Ca 2+ influx via transmembrane ion transport perturbations, but also severely damage the structural functions of mitochondria and the endoplasmic reticulum (ER) . Sustained ER stress further induces large amounts of Ca 2+ to be rapidly released from calcium pools, disrupting the ER calcium balance and resulting in severe [Ca 2+ ] i dysregulation .…”

Section: Introductionmentioning

confidence: 99%

1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic Acid Acetoxymethyl Ester Loaded Reactive Oxygen Species Responsive Hyaluronic Acid–Bilirubin Nanoparticles for Acute Kidney Injury Therapy via Alleviating Calcium Overload Mediated Endoplasmic Reticulum Stress

Wang

Yan

et al. 2022

ACS Nano

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Calcium overload is one of the early determinants of the core cellular events that contribute to the pathogenesis of acute kidney injury (AKI), which include oxidative stress, ATP depletion, calcium overload, and inflammatory response with self-amplifying and interactive feedback loops that ultimately lead to cellular injury and renal failure. Excluding adjuvant therapy, there are currently no approved pharmacotherapies for the treatment of AKI. Using an adipic dihydride linker, we modified the hyaluronic acid polymer chain with a potent antioxidant, bilirubin, to produce an amphiphilic conjugate. Subsequently, we developed a kidney-targeted and reactive oxygen species (ROS)-responsive drug delivery system based on the flash nanocomplexation method to deliver a well-known intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM, BA), with the goal of rescuing renal cell damage via rapidly scavenging of intracellularly overloaded Ca 2+ . In the ischemia−reperfusion (I/R) induced AKI rat model, a single dose of as-prepared formulation (BA 100 μg•kg −1 ) 6 h post-reperfusion significantly reduced renal function indicators by more than 60% within 12 h, significantly alleviated tissular pathological changes, ameliorated tissular oxidative damage, significantly inhibited apoptosis of renal tubular cells and the expression of renal tubular marker kidney injury molecule 1, etc., thus greatly reducing the risk of kidney failure. Mechanistically, the treatment with BA-loaded NPs significantly inhibited the activation of the ER stress cascade response (IRE1-TRAF2-JNK, ATF4-CHOP, and ATF6 axis) and regulated the downstream apoptosisrelated pathway while also reducing the inflammatory response. The BA-loaded NPs hold great promise as a potential therapy for I/R injury-related diseases. continued...

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Secretory pathway Ca2+-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry

Cited by 10 publications

References 55 publications

Marine-Derived Stichloroside C2 Inhibits Epithelial–Mesenchymal Transition and Induces Apoptosis through the Mitogen-Activated Protein Kinase Signalling Pathway in Triple-Negative Breast Cancer Cells

Marine-Derived Stichloroside C2 Inhibits Epithelial–Mesenchymal Transition and Induces Apoptosis through the Mitogen-Activated Protein Kinase Signalling Pathway in Triple-Negative Breast Cancer Cells

Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic Acid Acetoxymethyl Ester Loaded Reactive Oxygen Species Responsive Hyaluronic Acid–Bilirubin Nanoparticles for Acute Kidney Injury Therapy via Alleviating Calcium Overload Mediated Endoplasmic Reticulum Stress

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