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Developmental Biology - Mitochondria
Starving Cancer
A possible new target for cancer therapy...
Fighting cancer often means using techniques that target the tumor and prevent it from growing and spreading to other parts of the body. No small feat. The American Cancer Society predicts about 1.8 million new cases of cancer in 2020, which underscores our need to identify more ways to outsmart runaway cells.
Research from the University of California Santa Barbara may be helping by identifying a cell mechanism that, if it can, will interrupt the cascade of cancer signals proliferating tumor cells — starving malignant cells to death. This research is published in the journal Science Signaling.
"This particular approach is unique in that it targets mitochondria."
Armen Zakarian PhD, Professor, Organic Chemistry, Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, USA; and co-author.
Cancer therapy strategies use chemotherapy to damage cancer cell genes, rendering cells unable to replicate. According to Zakarian, targeting the access of cancer cells to energy they need to replicate — is a relatively new strategy, and under intense research.
The molecular workhorses modeling this new idea are sea sponges - Xestospongin B (XeB). First isolated years ago by study co-author Jordi Molgó, a molecule in the sponge was subsequently found to inhibit the effects on inositol triphosphate (IP3) receptors located on a cell organelle called the endoplasmic reticulum (ER). But, supply of the XeB molecule has gotten low. Production by marine sponges is not guaranteed, and attempts to find enough of the molecule were coming up short.
Zakarian's lab determined using XeB to block activation of IP3 receptors, prevented transport of calcium ions from the ER to mitochondria - a signal that kick starts production of chemical energy (ATP) and cell survival.
ER-to-mitochondria calcium ion transport is essential also to typical oxidative phosphorylation - a type of metabolism normal cells, and some cancer cells, use for energy.
Inhibiting inositol triphosphate receptors and lowering calcium ion uptake reduces ATP, and its prolonged inhibition "generates a bioenergetic crisis resulting in 70% cell death" accoring to research on tumorigenic breast and prostate cells. While the energy needs of non-cancerous cells exposed to XeB or a similar inhibitor would also be affected, the energy requirements of cancer cells are more vulnerable.
"Because cancer cells have high-energy demands, and an increased metabolic need for cell replication, they begin the process of cell death. Normal cells can survive a period of energetic stress and recover."
Armen Zakarian PhD
Finding that ER-to-mitochondria calcium flow is critical for multiple metabolic cancer pathways suggests this mechanism could be an important target for future cancer therapies, and possibly some cancer subtypes resistant to current chemotherapies. The research is still ongoing.
"We're going to collect data on the effects of xestospongin on cancer cells and on neurodegeneration. Our long-term goals will be in developing therapeutics."
Armen Zakarian PhD
Abstract
Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsP3R activity or mitochondrial Ca2+ uptake increased ?-ketoglutarate (?KG) abundance and the NAD+/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)–to–mitochondria Ca2+ transfer promoted optimal ?KG dehydrogenase (?KGDH) activity. Reducing mitochondrial Ca2+ inhibited ?KGDH activity and increased NAD+, which induced SIRT1-dependent autophagy in both OXPHOS-competent and OXPHOS-defective cells. Whereas autophagic flux in OXPHOS-competent cells promoted cell survival, it was impaired in OXPHOS-defective cells because of inhibition of autophagosome-lysosome fusion. Inhibition of ?KGDH and impaired autophagic flux in OXPHOS-defective cells resulted in pronounced cell death in response to interruption of constitutive flux of Ca2+ from ER to mitochondria. These results demonstrate that mitochondria play a fundamental role in maintaining bioenergetic homeostasis of both OXPHOS-competent and OXPHOS-defective cells, with Ca2+ regulation of ?KGDH activity playing a pivotal role. Inhibition of ER-to-mitochondria Ca2+ transfer may represent a general therapeutic strategy against cancer cells regardless of their OXPHOS status.
Authors
Cesar Cardenas, Alenka Lovy, Eduardo Silva-Pavez, Felix Urra, Craig Mizzoni, Ulises Ahumada-Castro, Galdo Bustos, Fabian Ja?a, Pablo Cruz, Paula Farias, Elizabeth Mendoza, Hernan Huerta, Paola Murgas, Martin Hunter, Melany Rios, Oscar Cerda, Irene Georgakoudi, Armen Zakarian, Jordi Molgó and J. Kevin Fosket.
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Jul 28 2020 Fetal Timeline Maternal Timeline News
 The sea sponge Xestospongin B (XeB) produces a molecule that inhibits a cell receptor on the endoplasmic reticulum (ER) preventing calcium from being transferred to mitochondria. However, sea sponges are in short supply. CREDIT Breast Cancer News.
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