Abstract:Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease, with an annual incidence of approximately 44,000 cases in the United States, and over 650,000 worldwide. While strides have been made in surgical techniques, refinement of radiation delivery and intensification of local-regional treatment with chemotherapeutic strategies, a significant number of patients succumb to distant metastasis and local-regional failure. Thus, there is a compelling need for new treatment regimens that ta… Show more
“…This result suggests that EZH2 suppresses STAT3 activation in a cell-autonomous manner without circuit level alterations. To determine whether STAT3-upstream kinases are required for pY705-STAT3 induction in shEZH2 cell lines, we incubated cells with either WP1066 (an analogue of the JAK2 inhibitor AG490 51–53 ) or CP690550 citrate (a small molecule inhibitor of JAK1/3 kinase activity 4,5,54 ). WP1066 did not impact STAT3 phosphorylation in shEZH2 cells at any concentration tested (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…This activation is not via secretion of soluble factors as swapping media from control and knockdown cells fails to activate STAT3 (data not shown). WP1066, a JAK2 inhibitor [51][52][53] fails to suppress activated STAT3 in shEZH2 cells whereas CP690550 (a JAK1/3 inhibitor) (Fig. 4B-C) and direct knockdown of JAK1 (Fig.…”
Section: Transient Jak Inhibition Acutely Post-se Rescues Epileptic P...mentioning
confidence: 99%
“…WP1066 (an analogue of the JAK2 inhibitor AG490 [40][41][42] ) or CP690550 citrate (a small molecule inhibitor of JAK1/3 kinase activity [43][44][45] ). WP1066 did not impact pSTAT3 in shEZH2 cells at any concentration tested (Fig.…”
Section: Fig 4 Jak/stat Signaling Is Reactivated and Targetable In Ch...mentioning
Epilepsy is the 4th most prevalent neurological disorder with over 50 million cases worldwide. While a number of drugs exist to suppress seizures, approximately 1/3 of patients remain drug resistant, and no current treatments are disease modifying. Using network and systems-based approaches, we find that the histone methylase EZH2 suppresses epileptogenesis and slows disease progression, via repression of JAK1 and STAT3 signaling in hippocampal neurons. Pharmacological inhibition of JAK1 with the orally available, FDA -approved drug CP690550 (Tofacitinib) virtually eliminates behavioral and electrographic seizures after the onset of epilepsy in a preclinical rodent model of acquired epilepsy. Overall, identification of an endogenous protective response to status epilepticus in the form of EZH2 induction has highlighted a critical role for the JAK1 kinase in epilepsy. Targeting JAK1 with CP690550 has a profound therapeutic effect on spontaneous, recurrent seizures.
“…This result suggests that EZH2 suppresses STAT3 activation in a cell-autonomous manner without circuit level alterations. To determine whether STAT3-upstream kinases are required for pY705-STAT3 induction in shEZH2 cell lines, we incubated cells with either WP1066 (an analogue of the JAK2 inhibitor AG490 51–53 ) or CP690550 citrate (a small molecule inhibitor of JAK1/3 kinase activity 4,5,54 ). WP1066 did not impact STAT3 phosphorylation in shEZH2 cells at any concentration tested (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…This activation is not via secretion of soluble factors as swapping media from control and knockdown cells fails to activate STAT3 (data not shown). WP1066, a JAK2 inhibitor [51][52][53] fails to suppress activated STAT3 in shEZH2 cells whereas CP690550 (a JAK1/3 inhibitor) (Fig. 4B-C) and direct knockdown of JAK1 (Fig.…”
Section: Transient Jak Inhibition Acutely Post-se Rescues Epileptic P...mentioning
confidence: 99%
“…WP1066 (an analogue of the JAK2 inhibitor AG490 [40][41][42] ) or CP690550 citrate (a small molecule inhibitor of JAK1/3 kinase activity [43][44][45] ). WP1066 did not impact pSTAT3 in shEZH2 cells at any concentration tested (Fig.…”
Section: Fig 4 Jak/stat Signaling Is Reactivated and Targetable In Ch...mentioning
Epilepsy is the 4th most prevalent neurological disorder with over 50 million cases worldwide. While a number of drugs exist to suppress seizures, approximately 1/3 of patients remain drug resistant, and no current treatments are disease modifying. Using network and systems-based approaches, we find that the histone methylase EZH2 suppresses epileptogenesis and slows disease progression, via repression of JAK1 and STAT3 signaling in hippocampal neurons. Pharmacological inhibition of JAK1 with the orally available, FDA -approved drug CP690550 (Tofacitinib) virtually eliminates behavioral and electrographic seizures after the onset of epilepsy in a preclinical rodent model of acquired epilepsy. Overall, identification of an endogenous protective response to status epilepticus in the form of EZH2 induction has highlighted a critical role for the JAK1 kinase in epilepsy. Targeting JAK1 with CP690550 has a profound therapeutic effect on spontaneous, recurrent seizures.
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