Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways

2011 ◽  
Vol 226 (11) ◽  
pp. 2762-2781 ◽  
Author(s):  
James A. McCubrey ◽  
Linda S. Steelman ◽  
C. Ruth Kempf ◽  
William H. Chappell ◽  
Stephen L. Abrams ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Mtor Signaling ◽  
Therapeutic Resistance

AKIP1 promotes cell proliferation, invasion, stemness and activates PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer

2021 ◽  
Author(s):  
Jiabin Zhao ◽  
Binjiahui Zhao ◽  
Limin Hou
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Mtor Signaling ◽  
Sequencing Analysis ◽  
Lncap Cells ◽  
Oncogenic Signaling ◽  
Interacting Protein

Abstract Background: The study aimed to examine the molecular mechanism and clinical significance of A-kinase interacting protein 1 (AKIP1) in prostate cancer. Methods: The effect of AKIP1 on cell proliferation, migration, invasion, apoptosis and stemness was determined by overexpressing and knocking down AKIP1 in LNCaP and 22Rv1 cells via lentivirus infection. Furthermore, differentially expressed genes (DEGs) by AKIP1 modification were determined using RNA sequencing. Besides, the correlation of AKIP1 with clinicopathological features and prognosis in 130 prostate cancer patients was assessed. Results: AKIP1 expression was increased in VCaP, LNCaP, DU145 cells while similar in 22Rv1 cells compared with RWPE-1 cells. Furthermore, AKIP1 overexpression promoted 22Rv1 and LNCaP cell proliferation, invasion, but inhibited apoptosis; meanwhile, AKIP1 overexpression increased CD133+ cell rate and enhanced spheres formation efficiency in 22Rv1 and LNCaP cells. Reversely, AKIP1 knockdown exhibited the opposite effect in 22Rv1 and LNCaP cells. Further RNA sequencing analysis exhibited that AKIP1-modified DEGs were enriched in the oncogenic signaling pathways related to prostate cancer, such as PI3K-Akt, MEK/ERK, mTOR signaling pathways. The following western blot indicated that AKIP1 overexpression activated while its knockdown blocked PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer cells. Clinically, AKIP1 was upregulated in the prostate tumor tissues compared with paired adjacent tissues, and its tumor high expression correlated with increased pathological T, pathological N stage and poor prognosis in prostate cancer patients. Conclusion: AKIP1 promotes cell proliferation, invasion, stemness, activates PI3K-Akt, MEK/ERK, mTOR signaling pathways and correlates with worse tumor features and prognosis in prostate cancer.

Repetitive restriction of muscle blood flow enhances mTOR signaling pathways in a rat model

2016 ◽  
Vol 31 (10) ◽  
pp. 1685-1695 ◽  
Author(s):  
Toshiaki Nakajima ◽  
Tomohiro Yasuda ◽  
Seiichiro Koide ◽  
Tatsuya Yamasoba ◽  
Syotaro Obi ◽  
...  
Keyword(s):  
Blood Flow ◽  
Signaling Pathways ◽  
Rat Model ◽  
Muscle Blood Flow ◽  
Mtor Signaling

Peruvoside targets apoptosis and autophagy through MAPK Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways in human cancers

Life Sciences ◽  
2020 ◽  
Vol 241 ◽  
pp. 117147 ◽  
Author(s):  
Dhanasekhar Reddy ◽  
Ranjith Kumavath ◽  
Tuan Zea Tan ◽  
Dinakara Rao Ampasala ◽  
Alan Prem Kumar
Keyword(s):  
Signaling Pathways ◽  
Mtor Signaling ◽  
Human Cancers

scholarly journals Rehmannia glutinosa Libosch Extracts Prevent Bone Loss and Architectural Deterioration and Enhance Osteoblastic Bone Formation by Regulating the IGF-1/PI3K/mTOR Pathway in Streptozotocin-Induced Diabetic Rats

2019 ◽  
Vol 20 (16) ◽  
pp. 3964 ◽  
Author(s):  
Wan Gong ◽  
Naidan Zhang ◽  
Gang Cheng ◽  
Quanlong Zhang ◽  
Yuqiong He ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Signaling Pathways ◽  
Bone Microarchitecture ◽  
Diabetic Rats ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Rehmannia Glutinosa ◽  
Mineral Density ◽  
Rehmannia Glutinosa Libosch

Rehmanniae Radix Praeparata (RR, named as Shudihuang in traditional Chinese medicine), the steamed roots of Rehmannia glutinosa Libosch (Scrophulariaceae), has been demonstrated to have anti-diabetic and anti-osteoporotic activities. This study aimed to explore the protective effect and underlying mechanism of RR on diabetes-induced bone loss. It was found that RR regulated the alkaline phosphatase activity and osteocalcin level, enhanced bone mineral density, and improved the bone microarchitecture in diabetic rats. The catalpol (CAT), acteoside (ACT), and echinacoside (ECH) from RR increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells injured by high glucose and promoted the production of IGF-1 and expression of related proteins in BMP and IGF-1/PI3K/mammalian target of rapamycin complex 1 (mTOR) signaling pathways. The verifying tests of inhibitors of BMP pathway (noggin) and IGF-1/PI3K/mTOR pathway (picropodophyllin) and molecular docking of IGF-1R further indicated that CAT, ACT, and ECH extracted from RR enhanced bone formation by regulating IGF-1/PI3K/mTOR signaling pathways. These findings suggest that RR may prove to be a promising candidate drug for the prevention and treatment of diabetes-induced osteoporosis.

Lanthanum chloride induces autophagy in rat hippocampus through ROS-mediated JNK and AKT/mTOR signaling pathways

Metallomics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 439-453 ◽  
Author(s):  
Xiang Gao ◽  
Jinghua Yang ◽  
Yingqi Li ◽  
Miao Yu ◽  
Shiyu Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathways ◽  
Learning And Memory ◽  
Memory Impairment ◽  
Mtor Signaling ◽  
Lanthanum Chloride ◽  
Rat Hippocampus ◽  
Central Nervous System Damage

Lanthanum (La) can cause central nervous system damage in rats and lead to learning and memory impairment, but the relevant mechanisms have not been fully elucidated.

scholarly journals Critical role of mTOR, PPARγ and PPARδ signaling in regulating early pregnancy decidual function, embryo viability and feto-placental growth

2018 ◽  
Vol 24 (6) ◽  
pp. 327-340 ◽  
Author(s):  
Sabrina L Roberti ◽  
Romina Higa ◽  
Verónica White ◽  
Theresa L Powell ◽  
Thomas Jansson ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Mtor Signaling ◽  
Embryo Viability ◽  
Mtor Inhibition ◽  
Resorption Rate ◽  
Ppar Signaling ◽  
Post Implantation ◽  
Implantation Period ◽  
Embryo Resorption

Abstract STUDY QUESTION What are the consequences of inhibiting mTOR, the mechanistic target of rapamycin (mTOR), and the peroxisome proliferator activated receptor gamma (PPARγ) and PPARδ pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? SUMMARY ANSWER mTOR inhibition from Days 7 to 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on Day 9 of pregnancy and resulted in embryo resorption by Day 14 of pregnancy. PPARγ and PPARδ inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on Day 14 of pregnancy. WHAT IS KNOWN ALREADY Although mTOR, PPARγ and PPARδ are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. STUDY DESIGN, SIZE, DURATION Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARγ inhibitor, 0.001 mg/kg, sc), GSK0660 (PPARδ inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from Days 7 to 9 of pregnancy and the studies were performed on Day 9 of pregnancy (n = 7 per group) or Day 14 of pregnancy (n = 7 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS On Day 9 of pregnancy, rat decidua were collected and prepared for western blot and immunohistochemical studies. On Day 14 of pregnancy, the resorption rate, number of viable fetuses, crown–rump length and placental and decidual weights were determined. MAIN RESULTS AND THE ROLE OF CHANCE Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on Day 9 of pregnancy but had resorbed by Day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in Day 9 of pregnancy. This treatment also reduced feto-placental growth on Day 14 of pregnancy, revealing the relevance of PPARγ signaling in sustaining post-implantation growth. Moreover, following inhibition of PPARδ, PLIN2 levels were decreased and mTOR complex 1 and 2 signaling was altered in decidua on Day 9 of pregnancy. On Day 14 of pregnancy, PPARδ inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARδ in sustaining post-implantation development. LARGE SCALE DATA Not applicable. LIMITATIONS, REASONS FOR CAUTION This is an in vivo animal study and the relevance of the results for humans remains to be established. WIDER IMPLICATIONS OF THE FINDINGS The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARγ and PPARδ signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation (Grants CONICET-NIH-2014 and CONICET-NIH-2017) to A.J. and T.J. The authors have no conflicts of interest.

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