Molecular Mechanisms Underlying Cell Survival During Endoplasmic Reticulum Stress
Project Number5SC3GM139707-04
Contact PI/Project LeaderBHANDARI, DEEPALI
Awardee OrganizationCALIFORNIA STATE UNIVERSITY LONG BEACH
Description
Abstract Text
ABSTRACT
Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced by our cells both
under normal physiological conditions such as in professional secretory cells and disease states
such as cancer, diabetes and neurodegeneration. Upon facing ER stress, cells initially attempt to
restore normal function by activating a conserved signaling pathway called the unfolded protein
response (UPR). However, if the stress becomes chronic and homeostasis is not restored within
a reasonable timeframe, the UPR ultimately commits cells to programmed cell death. How cells
make this life-or-death decision remains an exciting yet poorly understood phenomenon. Cancer
cells exhibit ER stress due to their high rates of glucose metabolism and hypoxic conditions
resulting in accumulation of underglycosylated, misfolded proteins in the ER. The ability of cancer
cells to successfully adapt to ER stress and continue to survive has been correlated to their
invasiveness/malignancy and chemoresistance. Thus, to be able to design effective molecularly
targeted therapeutic strategies, it is crucial to delineate the mechanisms that endow cancer cells
with cytoprotection in the face of ER stress. The main objective of this proposal is to investigate
the molecular mechanisms that play a decisive role in promoting cell survival through ER stress.
With the central hypothesis that the pro-survival Akt pathway regulates the UPR to determine the
overall cell fate, we will (A) Aim 1: investigate the role of Akt in regulation of signals originating
from the UPR sensors in response to stress (B) Aim 2: determine the mechanism by which Akt is
activated in a non-canonical manner during ER stress. Our results will potentially lead to important
revelations as to how cancer cells gain a cytoprotective advantage during ER stress resulting in
prolonged survival. The successful completion of our proposal will advance the field in terms of
enhancing our fundamental knowledge of a fascinating cell biological process as well as finding
new and key targets for curbing cancer cell survival.
Public Health Relevance Statement
PROJECT NARRATIVE
Cancer is the second leading cause of mortality worldwide, with an estimated 9.6 million cancer-
related deaths worldwide in 2018 (source – the World Health Organization). One of the major
hurdles in treatment of cancer is the cancer cell’s ability to survive under adverse conditions and
acquisition of drug resistance. Our proposal aims to study the mechanism(s) by which cancer
cells successfully adapt to stress and maintain viability. The successful completion of our studies
may provide new targets for therapeutic intervention in cancer treatment.
NIH Spending Category
No NIH Spending Category available.
Project Terms
Antineoplastic AgentsApoptosisBiochemicalBiological AssayBiological ProcessCancer PrognosisCell DeathCell Death InductionCell PhysiologyCell SurvivalCellsCellular StressCellular biologyCentrifugationCessation of lifeChemoresistanceChronicClinical TrialsCytoprotectionDataDegradation PathwayDiabetes MellitusDiseaseEndoplasmic ReticulumEndowmentExhibitsFunctional disorderGerm CellsGoalsHomeostasisHypoxiaImmunofluorescence MicroscopyIn SituKnowledgeLifeLigationLocationLuciferasesMalignant NeoplasmsMammalian CellMediatingMolecularMolecular ChaperonesNerve DegenerationOutcomePathologicPathway interactionsPhasePhosphorylationPhysiologicalPlayPost-Translational Protein ProcessingProductionProteinsProteomicsPublishingRegulationReporterResearchRoleSecretory CellSignal PathwaySignal TransductionSiteSourceStressTechniquesTestingTherapeutic InterventionTimeTranslationsVesicleWestern BlottingWorkWorld Health Organizationacquired drug resistancecancer cellcancer therapycopingdesignendoplasmic reticulum stressexperiencefascinateglucose metabolismimprovedinsightmimeticsmisfolded proteinmolecular targeted therapiesmortalitymutantnew therapeutic targetnovelprogramsprotein foldingprotein protein interactionrecruitresponsesensorsmall moleculetimelinevirtual
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