The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation

Lin, Tsung-Chieh; Su, Chih-Chung; Wu, Pei; Lai, Tsung‐Ching; Pan, Wen Chi; Jan, Yi-Hua; Chang, Yu Chang; Yeh, Chi Tai; Chen, Chi Long; Ger, Luo Ping; Chang, Hong; Yang, Chang-Hao; Huang, Ming‐Shyan; Liu, Yu Peng; Lin, Yuan; Shyy, John Y.‐J.; Tsai, Ming‐Daw; Hsiao, Michael

doi:10.7554/elife.11288

Cited by 43 publications

(38 citation statements)

References 48 publications

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“…6H). We further show that, in a cohort of CRC patients, decreased tumor expression of CK1 α is associated with a worse prognosis, similar to what has been reported for a number of other human cancers (43–46). These findings validate CK1α as a novel therapeutic target in CRC and identify a cohort of patients most likely to benefit from treatment with a CK1α activator such as SSTC3.…”

Section: Discussionsupporting

confidence: 87%

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Orton

Neitzel

et al. 2017

Sci. Signal.

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Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.

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Section: Discussionsupporting

confidence: 87%

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Orton

Neitzel

et al. 2017

Sci. Signal.

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“…A case–control study showed a higher risk of developing breast cancer in women with two specific single nucleotide polymorphisms in the POLK gene compared with controls 48 . NIFK that encodes for a protein that functions in mitosis and progression of cell cycle 26 was found to be upregulated and associated with poor prognosis in lung cancer 49 . SRGN encodes for a proteoglycan in hematopoietic cells 26 and its overexpression is associated with poor prognosis in hepatocellular 50 , colorectal cancer 51 , non-small cell lung cancer 52 , and nasopharyngeal carcinoma 53 .…”

Section: Discussionmentioning

confidence: 99%

Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome

Mindikoğlu

Abdulsada

Jain

et al. 2020

Sci Rep

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Metabolic syndrome is characterized by central obesity, insulin resistance, elevated blood pressure, and dyslipidemia. Metabolic syndrome is a significant risk factor for several common cancers (e.g., liver, colorectal, breast, pancreas). Pharmacologic treatments used for the components of the metabolic syndrome appear to be insufficient to control cancer development in subjects with metabolic syndrome. Murine models showed that cancer has the slowest progression when there is no food consumption during the daily activity phase. Intermittent fasting from dawn to sunset is a form of fasting practiced during human activity hours. To test the anticancer effect of intermittent fasting from dawn to sunset in metabolic syndrome, we conducted a pilot study in 14 subjects with metabolic syndrome who fasted (no eating or drinking) from dawn to sunset for more than 14 h daily for four consecutive weeks. We collected serum samples before 4-week intermittent fasting, at the end of 4th week during 4-week intermittent fasting and 1 week after 4-week intermittent fasting. We performed serum proteomic analysis using nano ultra-high performance liquid chromatography-tandem mass spectrometry. We found a significant fold increase in the levels of several tumor suppressor and DNA repair gene protein products (GP)s at the end of 4th week during 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent fasting (CALU, CALR, IGFBP4, SEMA4B) compared with the levels before 4-week intermittent fasting. We also found a significant reduction in the levels of tumor promoter GPs at the end of 4th week during 4-week intermittent fasting (POLK, CD109, CAMP, NIFK, SRGN), and 1 week after 4-week intermittent fasting (CAMP, PLAC1) compared with the levels before 4-week intermittent fasting. Fasting from dawn to sunset for four weeks also induced an anti-diabetes proteome response by upregulating the key regulatory proteins of insulin signaling at the end of 4th week during 4-week intermittent fasting (VPS8, POLRMT, IGFBP-5) and 1 week after 4-week intermittent fasting (PRKCSH), and an anti-aging proteome response by upregulating H2B histone proteins 1 week after 4-week intermittent fasting. Subjects had a significant reduction in body mass index, waist circumference, and improvement in blood pressure that co-occurred with the anticancer, anti-diabetes, and anti-aging serum proteome response. These findings suggest that intermittent fasting from dawn to sunset actively modulates the respective genes and can be an adjunct treatment in metabolic syndrome. Further studies are needed to test the intermittent fasting from dawn to sunset in the prevention and treatment of metabolic syndrome-induced cancers.

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“…Compared with the control group, there were two up-regulated ( Mki67 and Dixdc1 ) and two down-regulated ( Foxd3 and Gadd45a ) cell cycle-related genes in the Smo-OE group. Mki67 , which encodes the nuclear protein ki67 (a marker for proliferating cells; Lin et al, 2016 ), was significantly up-regulated in the Hedgehog-activation group.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog Signaling Promotes the Proliferation and Subsequent Hair Cell Formation of Progenitor Cells in the Neonatal Mouse Cochlea

Chen

Lü

Guo

et al. 2017

Front. Mol. Neurosci.

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Hair cell (HC) loss is the major cause of permanent sensorineural hearing loss in mammals. Unlike lower vertebrates, mammalian cochlear HCs cannot regenerate spontaneously after damage, although the vestibular system does maintain limited HC regeneration capacity. Thus HC regeneration from the damaged sensory epithelium has been one of the main areas of research in the field of hearing restoration. Hedgehog signaling plays important roles during the embryonic development of the inner ear, and it is involved in progenitor cell proliferation and differentiation as well as the cell fate decision. In this study, we show that recombinant Sonic Hedgehog (Shh) protein effectively promotes sphere formation, proliferation, and differentiation of Lgr5+ progenitor cells isolated from the neonatal mouse cochlea. To further explore this, we determined the effect of Hedgehog signaling on cell proliferation and HC regeneration in cultured cochlear explant from transgenic R26-SmoM2 mice that constitutively activate Hedgehog signaling in the supporting cells of the cochlea. Without neomycin treatment, up-regulation of Hedgehog signaling did not significantly promote cell proliferation or new HC formation. However, after injury to the sensory epithelium by neomycin treatment, the over-activation of Hedgehog signaling led to significant supporting cell proliferation and HC regeneration in the cochlear epithelium explants. RNA sequencing and real-time PCR were used to compare the transcripts of the cochleae from control mice and R26-SmoM2 mice, and multiple genes involved in the proliferation and differentiation processes were identified. This study has important implications for the treatment of sensorineural hearing loss by manipulating the Hedgehog signaling pathway.

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The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation

Cited by 43 publications

References 48 publications

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome

Hedgehog Signaling Promotes the Proliferation and Subsequent Hair Cell Formation of Progenitor Cells in the Neonatal Mouse Cochlea

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