The MEK1-ERK MAP kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells

Mitsui, Hiroshi; Takuwa, Noriko; Maruyama, Toshiyuki; Maekawa, Hisato; Hirayama, Makoto; Sawatari, Takashi; Hashimoto, Naoaki; Takuwa, Yoh; Kimura, Satoshi

doi:10.1002/1097-0215(200102)9999:9999<::aid-ijc1143>3.0.co;2-o

Cited by 68 publications

(30 citation statements)

References 39 publications

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“…Treatment of human liver cancer cells with MEK1/2 inhibitor U0126 or PD98059, which inhibits MEK-MAPK activation, leads to a time- and dose-dependent reduction in cell proliferation and viability. Our data are in agreement with previous study [25] showing that in vitro treatment of HepG2 with MEK inhibitor PD98059 resulted in apoptosis. Furthermore, over-expression of activated MEK1 in HepG2 enhances tumor growth in vivo and confers resistance to U0126-induced apoptosis implicating the requirement of MEK-MAPK activity for liver cancer cells to survive and tumor growth in vivo .…”

Section: Discussionsupporting

confidence: 94%

“…However, over-expression of activated MEK1 enhances tumor growth in vivo and confers drug resistance in vitro . This is in agreement with early studies demonstrating that transient expression of active MEK1 into HepG2 prevented apoptosis in serum-deprived condition [25]. Because the in vitro growth rate is similar between pUSE-transfected cells and activated MEK1-tranfected cells, susceptibility to apoptosis and low basal MAPK phosphorylation may explain in part by the slower growth of the mock-transfected cells than activated MEK1-transfected cells in SCID mice.…”

Section: Discussionsupporting

confidence: 92%

“…Studies with small molecule inhibitors of MEK activity [19,20]. demonstrate a role for MEK in mediating expression of proteinases implicated in invasion and metastasis [21,22], and disruption of normal epithelial morphology [23,24]Treatment of HepG2 with PD98059 resulted in apoptosis [25]. No substrates of MEK have been identified other than p44/42 MAPK (Reviewed in [26]).…”

Section: Introductionmentioning

confidence: 99%

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Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: Its role in tumor progression and apoptosis

et al. 2003

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: Its role in tumor progression and apoptosis

et al. 2003

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“…Inhibition of MEK1/2 could also sensitize hepatoma cells to the death induced by ER-stress [156]. Moreover, active form of MEK1 prevented serum deprivation-induced death of hepatocarcinoma cells [157] and in HepG2, MEK/ERK activity has been reported to contribute to cisplatin induced death [158]. The MEK/ERK pathway has also been shown to protect transformed hepatocytes from TGF- β -induced apoptosis, a natural inducer of apoptosis in hepatocytes, produced in the liver by hepatic stellate cells [159].…”

Section: Roles Of the Mek1/2-erk1/2 Pathway In Hepatocellular Carcmentioning

confidence: 99%

The MAPK MEK1/2-ERK1/2 Pathway and Its Implication in Hepatocyte Cell Cycle Control

Guégan

Frémin

Baffet

2012

International Journal of Hepatology

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Primary cultures of hepatocytes are powerful models in studying the sequence of events that are necessary for cell progression from a G0-like state to S phase. The models mimic the physiological process of hepatic regeneration after liver injury or partial hepatectomy. Many reports suggest that the mitogen-activated protein kinase (MAPK) ERK1/2 can support hepatocyte proliferation in vitro and in vivo and the MEK/ERK cascade acts as an essential element in hepatocyte responses induced by the EGF. Moreover, its disregulation has been associated with the promotion of tumor cell growth of a variety of tumors, including hepatocellular carcinoma. Whereas the strict specificity of action of ERK1 and ERK2 is still debated, the MAPKs may have specific biological functions under certain contexts and according to the differentiation status of the cells, notably hepatocytes. In this paper, we will focus on MEK1/2-ERK1/2 activations and roles in normal rodent hepatocytes in vitro and in vivo after partial hepatectomy and in human hepatocarcinoma cells. The possible specificity of ERK1 and ERK2 in normal and transformed hepatocyte will be discussed in regard to other differentiated and undifferentiated cellular models.

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“…Intracellular signaling mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways have been recognized as important factors in liver cancer. 2 …”

mentioning

confidence: 99%

Feedback loops blockade potentiates apoptosis induction and antitumor activity of a novel AKT inhibitor DC120 in human liver cancer

et al. 2014

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The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca2+ via Ca2+/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment.

show abstract

The MEK1-ERK MAP kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells

Cited by 68 publications

References 39 publications

Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: Its role in tumor progression and apoptosis

Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: Its role in tumor progression and apoptosis

The MAPK MEK1/2-ERK1/2 Pathway and Its Implication in Hepatocyte Cell Cycle Control

Feedback loops blockade potentiates apoptosis induction and antitumor activity of a novel AKT inhibitor DC120 in human liver cancer

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