<i>RASSF6</i>promotes p21<sup>Cip1/Waf1</sup>-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma

Liang, Ying; Zheng, Lichun; Wu, Yuan; Li, Peng; Cao, Yun; Cao, Xue; Xie, Ping; Huang, Bi; Qian, Chao Nan

doi:10.4161/cc.28416

Cited by 23 publications

(18 citation statements)

References 54 publications

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“…RASSF6 binds directly to K-Ras via its RA domain and synergizes with activated K-Ras to induce apoptosis [168]. As with the other RASSF family members, RASSF6 exhibits tumor suppressor properties; over expression of RASSF6 inhibits cell proliferation and induces apoptosis whereas loss of RASSF6 promotes cell growth in vitro and tumor formation in vivo [55, 168, 170–173]. The mechanisms by which RASSF6 induces apoptosis are independent of the Hippo signaling pathway, as RASSF6 interacts with MST2 to inhibit Hippo signaling, an effect observed with the Drosophila RASSF protein [171, 174].…”

Section: Other Rassf Family Membersmentioning

confidence: 99%

“…As with RASSF1A, RASSF3 and NORE1A, RASSF6 forms a complex with MDM2, promoting its ubiquitination and subsequent degradation, thereby regulating the cell cycle and inducing apoptosis [172]. Additional apoptotic pathways regulated by RASSF6 may be mediated by JNK signaling [173]. RASSF2 also activates JNK signaling and induces apoptosis independently of the Hippo signaling pathway [154], therefore JNK signaling may be one potential mechanism by which Ras induces apoptosis through the RASSF proteins.…”

Section: Other Rassf Family Membersmentioning

confidence: 99%

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Ras signaling through RASSF proteins

Donninger

Schmidt

Mezzanotte

et al. 2016

Seminars in Cell & Developmental Biology

107

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There are six core RASSF family proteins that contain conserved Ras Association domains and may serve as Ras effectors. They lack intrinsic enzymatic activity and appear to function as scaffolding and localization molecules. While initially being associated with pro-apoptotic signaling pathways such as Bax and Hippo, it is now clear that they can also connect Ras to a surprisingly broad range of signaling pathways that control senescence, inflammation, autophagy, DNA repair, ubiquitination and protein acetylation. Moreover, they may be able to impact the activation status of pro-mitogenic Ras effector pathways, such as the Raf pathway. The frequent epigenetic inactivation of RASSF genes in human tumors disconnects Ras from pro-death signaling systems, enhancing Ras driven transformation and metastasis. The best characterized members are RASSF1A and RASSF5 (NORE1A).

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Section: Other Rassf Family Membersmentioning

confidence: 99%

Section: Other Rassf Family Membersmentioning

confidence: 99%

Ras signaling through RASSF proteins

Donninger

Schmidt

Mezzanotte

et al. 2016

Seminars in Cell & Developmental Biology

107

View full text Add to dashboard Cite

show abstract

“…Mechanistically, this combination treatment triggered intracellular ROS accumulation and subsequently activated the caspase signalling cascade, leading to cancer cell apoptosis. Moreover, p21, the CDK inhibitor belonging to the Cip/Kip family, has now been reported to play additional and key roles in other important pathways, including oncogenic properties, apoptosis and DNA repair (Cheng et al, 2010;Stivala et al, 2012;Lee et al, 2013a;Liang et al, 2014). Overexpression of p21(Cip1) maintains cells longer in the G1 phase and attenuates shikonin-induced apoptosis.…”

Section: Figurementioning

confidence: 99%

Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

Mei

Chen

Wang

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSETetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. EXPERIMENTAL APPROACHCultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. KEY RESULTSCombinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21 −/− HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. CONCLUSIONS AND IMPLICATIONSThe combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment.

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“…MOAP1 knockdown attenuates RASSF6-induced apoptosis but does not reduce it in a p53-negative background, suggesting that MOAP1 functions in the same pathway as p53 [ 9 ]. In renal carcinoma cells, RASSF6 activates c-Jun N -terminal kinase (JNK) and JNK inhibitor suppresses RASSF6-induced apoptosis [ 31 ]. RASSF2 also activates JNK and induces apoptosis independently of the Hippo pathway [ 22 ].…”

Section: Rassf6 and Other Pro-apoptotic Moleculesmentioning

confidence: 99%

RASSF6; the Putative Tumor Suppressor of the RASSF Family

Iwasa¹,

Jiang²,

Hata³

2015

Cancers

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Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are referred to as the C-RASSF proteins. The C-RASSF proteins have the RA domain in the middle region and the Salvador/RASSF/Hippo domain in the C-terminal region. RASSF6 additionally harbors the PSD-95/Discs large/ZO-1 (PDZ)-binding motif. Expression of RASSF6 is epigenetically suppressed in human cancers and is generally regarded as a tumor suppressor. RASSF6 induces caspase-dependent and -independent apoptosis. RASSF6 interacts with mammalian Ste20-like kinases (homologs of Drosophila Hippo) and cross-talks with the Hippo pathway. RASSF6 binds MDM2 and regulates p53 expression. The interactions with Ras and Modulator of apoptosis 1 (MOAP1) are also suggested by heterologous protein-protein interaction experiments. RASSF6 regulates apoptosis and cell cycle through these protein-protein interactions, and is implicated in the NF-κB and JNK signaling pathways. We summarize our current knowledge about RASSF6 and discuss what common and different properties RASSF6 and the other C-RASSF proteins have.

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RASSF6promotes p21^Cip1/Waf1-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma

Cited by 23 publications

References 54 publications

Ras signaling through RASSF proteins

Ras signaling through RASSF proteins

Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

RASSF6; the Putative Tumor Suppressor of the RASSF Family

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RASSF6promotes p21Cip1/Waf1-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma

Cited by 23 publications

References 54 publications

Ras signaling through RASSF proteins

Ras signaling through RASSF proteins

Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

RASSF6; the Putative Tumor Suppressor of the RASSF Family

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RASSF6promotes p21^Cip1/Waf1-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma