Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

Joechle, Katharina; Jumaa, Huda; Thriene, Kerstin; Hellerbrand, Claus; Kulemann, Birte; Fichtner‐Feigl, Stefan; Lang, Sven A.; Guenzle, Jessica

doi:10.3389/fcell.2021.785979

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…For instance, adequate YAP signaling pathway inactivation and ERK, p38 signaling pathway activation are necessary to maintain cancer cell survival. It is well established that mTOR phosphorylation greatly contributes to the expression of MMP9 and cell invasion [ 33 , 34 ]. AKT–mTOR signaling upregulates MMP9 expression by promoting H3K27Ac and H3K56A on the MMP9 promoter region [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion

Xia,

Ye,

Zhao

et al. 2023

IJMS

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Molecules interacting with CasL (MICALs) are critical mediators of cell motility that act by cytoskeleton rearrangement. However, the molecular mechanisms underlying the regulation of cancer cell invasion remain elusive. The aim of this study was to investigate the potential role of one member of MICALs, i.e., MICALL2, in the invasion and function of ovarian cancer cells. We showed by bioinformatics analysis that MICALL2 expression was significantly higher in tissues of advanced-stage ovarian cancer and associated with poor overall survival of patients. MICALL2 was strongly correlated with the infiltration of multiple types of immune cells and T-cell exhaustion markers. Moreover, enrichment analyses showed that MICALL2 was involved in the tumor-related matrix degradation pathway. Mechanistically, MMP9 was identified as the target gene of MICALL2 for the regulation of invadopodium formation and SKOV3, HO-8910PM cell invasion. In addition, EGFR–AKT–mTOR signaling was identified as the downstream pathway of MICALL2 in the regulation of MMP9 expression. Furthermore, MICALL2 silencing promoted EGFR degradation; however, this effect was abrogated by treatment with the autophagy inhibitors acadesine and chloroquine diphosphate. Silencing of MICALL2 resulted in a suppressive activity of Rac1 while suppressing Rac1 activation attenuated the pro-EGFR, pro-MMP9, and proinvasive effects induced by the overexpression of MICALL2. Collectively, our results indicated that MICALL2 participated in the process of immune infiltration and invasion by ovarian cancer cells. Moreover, MICALL2 prevented EGFR degradation in a Rac1-dependent manner, consequently leading to EGFR–AKT–mTOR–MMP9 signaling activation and invadopodia-mediated matrix degradation.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion

Xia,

Ye,

Zhao

et al. 2023

IJMS

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“…Furthermore, it was found that 20d suppressed the cell migration in HCT116 cells in a time-dependent manner. Indeed, inhibition of the PI3K/AKT/mTOR pathway has also been found to suppress migration in other tumors including breast cancer 74 , bile duct cancer 75 , and osteosarcoma 76 . These findings indicate that 20d is a potential tumor suppressor in colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of tetrahydroquinolinones and tetrahydroquinolines with anticancer activity

Ryczkowska

Maciejewska

Olszewski

et al. 2022

Sci Rep

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Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8-tetrahydroquinolin-8-yl) N-(3-fluorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These findings suggest that this tetrahydroquinolinone can be an ideal lead compound for drug discovery based on quinone derivatives.

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“…The results of multiple clinical trials showed that second-generation 'rapalogs' possess effective pharmacokinetic properties and exert anticancer effects (72). Table I provides a list of different types of mTORC2 inhibitors to treat CRC (73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84), liver cancer (85-99), gallbladder cancer (100)(101)(102), GC (61,(103)(104)(105)(106), esophageal cancer (32,(107)(108)(109)(110), pancreatic cancer (111)(112)(113)(114)(115)(116)(117)(118)(119) and biliary tract cancer (120)(121)(122)(123). The therapeutic efficacy of rapalogs may be diminished by the pro-survival feedback loops that may be induced by the rapalogs' mTORC1-specific inhibition, such as the PI3K-Akt and PI3K-RAS-ERK pathways.…”

Section: Targeted Therapymentioning

confidence: 99%

Roles of Rictor alterations in gastrointestinal tumors (Review)

Cao,

Guo,

Min

et al. 2024

Oncol Rep

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Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re-sensitization of therapy-resistant cancers to be made possible.

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Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

Cited by 6 publications

References 51 publications

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion

Design, synthesis, and biological evaluation of tetrahydroquinolinones and tetrahydroquinolines with anticancer activity

Roles of Rictor alterations in gastrointestinal tumors (Review)

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