Targeting Akt in cancer for precision therapy

Hua, Hui; Zhang, Hongying; Chen, Jingzhu; Wang, Jiao; Liu, Jieya; Jiang, Yangfu

doi:10.1186/s13045-021-01137-8

Cited by 106 publications

(37 citation statements)

References 296 publications

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“…Whereas TGF-β may inhibit tumor cell growth at the early stage, it usually promotes cancer metastasis at late stages. As a TGF-β- and IGF-responsive gene, SNCG is more frequently overexpressed in advanced cancers and involved in the stabilization or activation of some oncogenes such as IGF-IR and Akt, which have critical roles in tumorigenesis and drug resistance 2 , 28 , 30 , 31 . Preclinical studies have demonstrated that SNCG can promote cancer metastasis 14 , 20 , 21 , 24 .…”

Section: Discussionmentioning

confidence: 99%

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Liu¹,

Shao²,

Zhang³

et al. 2022

Int. J. Biol. Sci.

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Gamma synuclein (SNCG) is a neuronal protein that is also aberrantly overexpressed in various types of human cancer. SNCG overexpression promotes cancer invasion and metastasis. However, the mechanisms that drive cancer metastasis upon SNCG expression remain elusive. Elucidation of the mechanisms underlying the promotion of cancer metastasis by SNCG may help discover therapeutic avenues for SNCG-overexpressed cancer. Here, we show that SNCG promotes transforming growth factor-β (TGF-β)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Mechanistically, SNCG promotes p38MAPK phosphorylation by interacting with the MAPK kinase 3/6 (MKK3/6) and prevents their degradation. SNCG knockdown leads to a decrease in TGF-β-induced phosphorylation of MKK3/6; and abrogates the induction of matrix metalloproteinase (MMP)-9 expression by TGF-β and its target gene Twist1. Furthermore, p38MAPK inhibition abrogates the promotion of MMP-9 expression and cancer cell invasion by SNCG. Both p38MAPK and MMP inhibitors can suppress the promotion of cancer cell invasion by SNCG. Finally, overexpression of SNCG in liver cancer cells promotes lung metastasis, which can be suppressed by the p38MAPK inhibitor. Together, our data uncover a previously unknown role of SNCG in promoting TGF-β-MKK3/6-p38MAPK signaling. This study highlights the critical role of p38MAPK in the promotion of cancer metastasis by SNCG, and indicates that p38MAPK inhibitor may serve as a potential therapeutic for SNCG-overexpressed cancer.

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Section: Discussionmentioning

confidence: 99%

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Liu¹,

Shao²,

Zhang³

et al. 2022

Int. J. Biol. Sci.

Self Cite

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“…In addition, PROTAC (proteolysis targeting chimera) was also developed to degrade AKT kinase [ 38 ]. For now, many clinical trials of AKT inhibitors are underway [ 39 ]. AKT inhibitors like capivasertib and ipatasertib are being tested in a phase-Ⅲ clinical trial.…”

Section: Discussionmentioning

confidence: 99%

A Novel Isaindigotone Derivative Displays Better Anti-Proliferation Activities and Induces Apoptosis in Gastric Cancer Cells

Yang

Zhou

et al. 2022

IJMS

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Isaindigotone is an alkaloid containing a pyrrolo-[2,1-b]quinazoline moiety conjugated with a benzylidene group and isolated from the root of Isatis indigotca Fort. However, further anticancer activities of this alkaloid and its derivatives have not been fully explored. In this work, a novel isaindigotone derivative was synthesized and three different gastric cell lines and one human epithelial gastric cell line were used to study the anti-proliferation effects of the novel isaindigotone derivative BLG26. HGC27 cells and AGS cells were used to further explore the potential mechanisms. BLG26 exhibited better anti-proliferation activities in AGS cells with a half-maximal inhibitory concentration (IC50) of 1.45 μM. BLG26 caused mitochondrial membrane potential loss and induced apoptosis in both HGC27 cells and AGS cells by suppressing mitochondrial apoptotic pathway and PI3K/AKT/mTOR axis. Acute toxicity experiment showed that LD50 (median lethal dose) of BLG26 was above 1000.0 mg/kg. This research suggested that BLG26 can be a potential candidate for the treatment of gastric cancer.

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“…In addition, AKT activation may confer resistance to anticancer agents such as the ER antagonists tamoxifen and fulvestrant. Combination of AKT inhibitors with tamoxifen and fulvestrant may improve their effectiveness [ 61 , 62 ]. Pan-mTORC1/2 inhibitors can also reverse endocrine resistance, chemoresistance and radiation resistance [ 63 ].…”

Section: Changes Of the Pam Pathway In Different Breast Cancer Subtypesmentioning

confidence: 99%

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

Zhu

et al. 2022

Cells

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Phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) (PAM) pathways play important roles in breast tumorigenesis and confer worse prognosis in breast cancer patients. The inhibitors targeting three key nodes of these pathways, PI3K, AKT and mTOR, are continuously developed. For breast cancer patients to truly benefit from PAM pathway inhibitors, it is necessary to clarify the frequency and mechanism of abnormal alterations in the PAM pathway in different breast cancer subtypes, and further explore reliable biomarkers to identify the appropriate population for precision therapy. Some PI3K and mTOR inhibitors have been approved by regulatory authorities for the treatment of specific breast cancer patient populations, and many new-generation PI3K/mTOR inhibitors and AKT isoform inhibitors have also been shown to have good prospects for cancer therapy. This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.

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Targeting Akt in cancer for precision therapy

Cited by 106 publications

References 296 publications

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

A Novel Isaindigotone Derivative Displays Better Anti-Proliferation Activities and Induces Apoptosis in Gastric Cancer Cells

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

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