title: INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells.
abstract: Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.
authors.forename: H J
authors.initials: HJ
authors.lastname: An
authors.forename: E K
authors.initials: EK
authors.lastname: Choi
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: S W
authors.initials: SW
authors.lastname: Hong
authors.forename: J H
authors.initials: JH
authors.lastname: Moon
authors.forename: J S
authors.initials: JS
authors.lastname: Shin
authors.forename: S H
authors.initials: SH
authors.lastname: Ha
authors.forename: K P
authors.initials: KP
authors.lastname: Kim
authors.forename: Y S
authors.initials: YS
authors.lastname: Hong
authors.forename: J L
authors.initials: JL
authors.lastname: Lee
authors.forename: E K
authors.initials: EK
authors.lastname: Choi
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: D H
authors.initials: DH
authors.lastname: Jin
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; C540383:ruxolitinib; C507904:JAK1 protein, human; D053613:Janus Kinase 1