p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector

Artemenko, Margarita; Zhong, Sophia S.W.; To, Sally K Y; Wong, Alice S.T.

doi:10.1016/j.canlet.2022.215593

Cited by 27 publications

(13 citation statements)

References 128 publications

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“…*p < .05, **p < .01. the phosphorylation of insulin receptor substrate 1 (IRS1) S1101 and desensitization of the insulin receptor. 22,43 S6K1-deficient mice are resistant to HFD-induced hyperglycemia and obesity. 44 We recently reported that gingerenone A, a natural product of the ginger extract, and astaxanthin, a natural, pigmented xanthophyll carotenoid commonly present in microalgae, yeasts, salmon, trout, krill, and other seafood, inhibit S6K1 activity, sensitize the insulin receptor, and increase glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

“…S6K1 has been implicated in playing an important role in the pathogenesis of hyperglycemia and obesity 22,43,44 . S6K1 is hyperactivated in the condition of overnutrition.…”

Section: Discussionmentioning

confidence: 99%

“…S6K1 expression is upregulated in the visceral adipose tissue in obesity and potentially promotes the expression of inflammatory cytokines 45 . Constitutive S6K1 activation leads to the phosphorylation of insulin receptor substrate 1 (IRS1) S1101 and desensitization of the insulin receptor 22,43 . S6K1‐deficient mice are resistant to HFD‐induced hyperglycemia and obesity 44 .…”

Section: Discussionmentioning

confidence: 99%

“…S6K1 has been implicated in playing important role in the pathogenesis of hyperglycemia and obesity. 22,43,44 S6K1 is hyperactivated in the condition of overnutrition. S6K1 expression is upregulated in the visceral adipose tissue in obesity and potentially promotes the expression of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

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Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Ji,

Chen,

You

et al. 2023

The FASEB Journal

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Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti‐obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3‐L1 adipocytes by activating TGF‐β‐activated kinase 1 (TAK1), AMP‐activated kinase (AMPK), and Unc‐51 like autophagy‐activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3‐L1 adipocytes, which was blocked by bafilomycin or by beclin‐1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1−/− embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K−/− mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide‐mediated anti‐obesity activity.

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Section: Discussionmentioning

confidence: 99%

“…S6K1 has been implicated in playing an important role in the pathogenesis of hyperglycemia and obesity 22,43,44 . S6K1 is hyperactivated in the condition of overnutrition.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Ji,

Chen,

You

et al. 2023

The FASEB Journal

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“…144 Meanwhile, OSCC cell growth is influenced by various proteins serving as targets, including SH3 domain-containing kinase binding protein 1 (SH3KBP1), 145 annexin A10, 146 fibroblast activation protein, 147 EGFR, 148 parathyroid hormone-related protein, 149 angiopoietin-like 3 (ANGPTL3), 150 quaking 5, 151 and 70-kDa ribosomal S6 kinase. 152 Aberrant inactivation of suppressor signaling TP53/RB, p16/Cyclin D1/Rb, and NOTCH are examples of suppressor signaling pathways. During the malignant transformation of OPMDs to OSCC, they become abnormally inactivated and downregulated.…”

Section: Genetic Alterations Drive the Occurrence Of Osccmentioning

confidence: 99%

Oral squamous cell carcinomas: state of the field and emerging directions

Tan,

Wang,

et al. 2023

Int J Oral Sci

151

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Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.

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Identification of an Alepterolic Acid Derivative as a Potent Anti‐Breast‐Cancer Agent via Inhibition of the Akt/p70^S6K Signaling Pathway

Wang,

Zhang,

et al. 2023

Chemistry & Biodiversity

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Alepterolic acid is a diterpene occurring in the fern Aleuritopteris argentea with potentially biological activity warrant further structural modification. In the present work, sixteen alepterolic acid derivatives were synthesized and evaluated for their anti‐cancer activities. Among them, N‐[m‐(trifluoromethoxy)phenyl] alepterolamide displayed comparable activity (IC50=4.20±0.21 μM) in MCF‐7 cells. Moreover, mechanistic investigations indicated this compound was significantly capable of diminishing cell proliferation and viability of MCF‐7 cells. After treatment with N‐[m‐(trifluoromethoxy)phenyl] alepterolamide, a significant increase in cleaved caspase‐9, cleaved caspase‐3, cleaved poly (ADP‐ribose) polymerase (PARP) and Bax/Bcl2 ratio were observed in MCF‐7 cells, leading to caspase‐dependent apoptotic pathways. Further studies showed this compound promoted cellular apoptosis and inhibited migration in MCF‐7 cells via modulation of Akt/p70S6K signaling pathway. All these results revealed the potential of N‐[m‐(trifluoromethoxy)phenyl] alepterolamide as an appealing therapeutic drug candidate for MCF‐7 breast cancer cells.

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p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector

Cited by 27 publications

References 128 publications

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Oral squamous cell carcinomas: state of the field and emerging directions

Identification of an Alepterolic Acid Derivative as a Potent Anti‐Breast‐Cancer Agent via Inhibition of the Akt/p70^S6K Signaling Pathway

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p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector

Cited by 27 publications

References 128 publications

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Oral squamous cell carcinomas: state of the field and emerging directions

Identification of an Alepterolic Acid Derivative as a Potent Anti‐Breast‐Cancer Agent via Inhibition of the Akt/p70S6K Signaling Pathway

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Resources

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Identification of an Alepterolic Acid Derivative as a Potent Anti‐Breast‐Cancer Agent via Inhibition of the Akt/p70^S6K Signaling Pathway