TY - JOUR
T1 - Ferroptosis in neurons and cancer cells is similar but differentially regulated by histone deacetylase inhibitors
AU - Zille, Marietta
AU - Kumar, Amit
AU - Kundu, Nandini
AU - Bourassa, Megan W.
AU - Wong, Victor S.C.
AU - Willis, Dianna
AU - Karuppagounder, Saravanan S.
AU - Ratan, Rajiv R.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the Xctransporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species-dependent death. Accordingly, pharmacological inhibitors of the Xctransporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy. Here, we show that ferroptotic death induced by the canonical ferroptosis inducer erastin is similar in HT1080 fibrosarcoma cells and primary cortical neurons although cell death is mediated more potently in cancer cells. Reducing the toxicity of ferroptosis inducers will require, among other things, the identification of agents that protect neurons from ferroptosis but exacerbate it in tumor cells. Although we show that a number of agents known to block ferroptosis in primary mouse neurons also inhibit ferroptosis in fibrosarcoma cells, class I histone deacetylase (HDAC) inhibitors selectively protect neurons while augmenting ferroptosis in cancer cells. Our results further suggest that cell death pathways induced by erastin in these two cell types are statistically identical to each other and identical to oxidative glutamate toxicity in neurons, where death is also mediated via inhibition of Xccystine transport. Together, these studies identify HDACs inhibitors as a novel class of agents to augment tumor suppression by ferroptosis induction and to minimize neuronal toxicity that could manifest as peripheral neuropathy or chemo brain.
AB - Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the Xctransporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species-dependent death. Accordingly, pharmacological inhibitors of the Xctransporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy. Here, we show that ferroptotic death induced by the canonical ferroptosis inducer erastin is similar in HT1080 fibrosarcoma cells and primary cortical neurons although cell death is mediated more potently in cancer cells. Reducing the toxicity of ferroptosis inducers will require, among other things, the identification of agents that protect neurons from ferroptosis but exacerbate it in tumor cells. Although we show that a number of agents known to block ferroptosis in primary mouse neurons also inhibit ferroptosis in fibrosarcoma cells, class I histone deacetylase (HDAC) inhibitors selectively protect neurons while augmenting ferroptosis in cancer cells. Our results further suggest that cell death pathways induced by erastin in these two cell types are statistically identical to each other and identical to oxidative glutamate toxicity in neurons, where death is also mediated via inhibition of Xccystine transport. Together, these studies identify HDACs inhibitors as a novel class of agents to augment tumor suppression by ferroptosis induction and to minimize neuronal toxicity that could manifest as peripheral neuropathy or chemo brain.
UR - http://www.scopus.com/inward/record.url?scp=85061872966&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0263-18.2019
DO - 10.1523/ENEURO.0263-18.2019
M3 - Journal articles
C2 - 30783618
AN - SCOPUS:85061872966
SN - 2373-2822
VL - 6
JO - eNeuro
JF - eNeuro
IS - 1
M1 - e0263-18.2019
ER -