Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells

Jin, Xiaohong; Gossett, Dana R.; Wang, Shaomeng; Yang, Dajun; Cao, Yang; Chen, J.; Guo, Ribo; Reynolds, R. Kevin; Lin, Jiayuh

doi:10.1038/sj.bjc.6602214

Cited by 71 publications

(57 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, more potent AKT inhibitors, such as small-molecule inhibitor API-59CJ-OMe (9-methoxy-2-methylellipticinium acetate; ref. 53), are being developed.…”

Section: Discussionmentioning

confidence: 99%

Concomitant Activation of the JAK/STAT, PI3K/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells

Saxena¹,

Sharma

Ding³

et al. 2007

Cancer Research

424

376

View full text Add to dashboard Cite

Various epidemiologic studies have shown that obesity is associated with hepatocellular carcinoma. Leptin, the key player in the regulation of energy balance and body weight control, also acts as a growth factor on certain organs in both normal and disease states. It is plausible that leptin acts to promote hepatocellular carcinogenesis directly affecting malignant properties of liver cancer cells. However, a direct role for leptin in hepatocellular carcinoma has not been shown. In this study, we analyzed the role of leptin and the mechanism(s) underlying its action in hepatocellular carcinoma cells, which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of both HepG2 and Huh7 cells and involves activation of signal transducers and activators of transcription 3 (STAT3), AKT, and extracellular signal-regulated kinase (ERK) signaling pathways. Leptin-induced phosphorylation of ERK and AKT was dependent on Janus-activated kinase (JAK)/STAT activation. Intriguingly, we also found that leptin potently induces invasion of hepatocellular carcinoma cells in Matrigel invasion and electric cell-substrate impedancesensing assays. Leptin-stimulated invasion was effectively blocked by pharmacologic inhibitors of JAK/STAT and, to a lesser extent, by ERK and phosphatidylinositol 3-kinase (PI3K) inhibition. Importantly, leptin also induced the migration of both HepG2 and Huh7 cells on fibronectin matrix. Inhibition of JAK/STAT, ERK, and PI3K activation using pharmacologic inhibitors effectively blocked leptin-induced migration of HepG2 and Huh7 cells. Taken together, these data indicate that leptin promotes hepatocellular carcinoma growth, invasiveness, and migration and implicate the JAK/STAT pathway as a critical mediator of leptin action. Our findings have potential clinical implications for hepatocellular carcinoma progression in obese patients. [Cancer Res 2007;67(6):2497-507]

show abstract

“…In addition, more potent AKT inhibitors, such as small-molecule inhibitor API-59CJ-OMe (9-methoxy-2-methylellipticinium acetate; ref. 53), are being developed.…”

Section: Discussionmentioning

confidence: 99%

Concomitant Activation of the JAK/STAT, PI3K/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells

Saxena¹,

Sharma

Ding³

et al. 2007

Cancer Research

424

376

View full text Add to dashboard Cite

show abstract

“…PD173074 had no effect on ERK1/2 or AKT activation in HEC1A cells. Due to the low level of phosphorylated AKT (Threonine 308) in HEC1A cells (13), the image shown here is an overexposure relative to the other pAKT blots presented. B, AN3CA cells were starved in 0.2% FBS overnight, pretreated with or without 1 Amol/L PD173074 for 1 h, and then stimulated with 1 nmol/L FGF7 and 10 Ag/mL heparin for 5 min.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation

et al. 2008

View full text Add to dashboard Cite

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

show abstract

“…It has also shown efficacy against ovarian carcinoma (Hu et al 2000). Also, more potent AKT inhibitors such as the small molecule inhibitor API-59CJ-OMe (9-methoxy-2-methylellipticinium acetate) (Jin et al 2004) are being developed.…”

Section: Discussionmentioning

confidence: 99%

Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways

Sharma¹,

Saxena²,

Vertino³

et al. 2006

Endocr Relat Cancer

152

144

View full text Add to dashboard Cite

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/ STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptinstimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.

show abstract

Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells

Cited by 71 publications

References 19 publications

Concomitant Activation of the JAK/STAT, PI3K/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells

Concomitant Activation of the JAK/STAT, PI3K/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells

Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation

Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways

Contact Info

Product

Resources

About