A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1

Wang, Jianrong; Whiteman, Mary W.; Lian, Huiqin; Wang, Guangxin; Singh, Amit Kumar; Huang, Dongyang; Denmark, Ted

doi:10.1074/jbc.m109.026013

Cited by 291 publications

(283 citation statements)

References 62 publications

Supporting

Mentioning

261

Contrasting

Order By: Relevance

“…Interestingly, the induction of an autophagy marker, LC-3, a mammalian homolog of yeast Atg8 (Aut7-Apg8), by TPA is mediated by the Ras-MAPK pathway (9,27). A recent study shows that depletion of ERK partially inhibited autophagy, whereas specific inhibition of MEK completely inhibited autophagy (28). As shown in this study, TPA induced the interaction of Pin1 with MEK and resulted in expression levels of LC-3 mRNA and protein (Fig.…”

Section: Discussionsupporting

confidence: 67%

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

Namgoong

Khanal

Cho

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Endocrine therapies, which inhibit estrogen receptor signaling, are the most common and effective treatments for estrogen receptor␣-positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance, and the precise mechanisms underlying endocrine therapy resistance remain incompletely understood. Here, we demonstrate that peptidyl-prolyl isomerase Pin1 is an important determinant of resistance to tamoxifen and show that Pin1 increases E2F-4-and Egr-1-driven expression of LC-3 as a result of an increased interaction with and phosphorylation of MEK1/2. In human tamoxifen-resistant breast cancer, our results show a significant correlation between Pin1 overexpression and high levels of LC-3. Promoter activity as well as expression levels of Pin1 were drastically higher in tamoxifen-resistant MCF7 cells than control MCF7 cells, as were levels of LC-3 mRNA and protein, an autophagy marker. Pin1 Breast cancer is one of the most common malignancies in women and the second most common cause of female cancerrelated deaths (1). However, deaths due to breast cancer have decreased because of the development of targeted therapies, including hormone therapy, in addition to conventional chemotherapy and surgical interventions (1). The majority of breast cancers in postmenopausal women express the estrogen receptors (ERs), 3 and after surgery, they can be treated with hormonal therapy alone, in the absence of more toxic chemotherapy, resulting in a relatively favorable prognosis (2). However, a significant fraction of these hormone-sensitive breast cancer patients will experience disease progression because of resistance to endocrine agents, such as tamoxifen, resulting in mortality (3). Tamoxifen is currently the most widely prescribed, orally active, selective ER modulator for the treatment of breast cancer (4). Although tamoxifen is an ER antagonist in breast tissue, it can also be a partial agonist. Antagonist activity enables the drug to block ER-mediated transcription and cancer cell growth in ER-positive breast cancer cells (5). However, tamoxifen resistance might occur when its agonistic activity overcomes its antagonistic effect (4). This variability could be related, in part, to the cellular milieu of ER co-activators and co-repressors (6). For example, increased levels of co-activators, such as SRC-3, enhance the estrogen agonist properties of tamoxifen, whereas decreased levels of co-repressors, such as SMRT (silencing mediator for retinoid and thyroid receptors) and nuclear receptor corepressor, correlate with acquired tamoxifen resistance (6).Pin1 has two domains: a peptidyl-prolyl cis/trans-isomerase domain at its COOH terminus responsible for isomerization and a WW domain at the NH 2 terminus, which functions as a binding element specific for Ser(P)/Thr-Pro motifs (7). Through these two domains, Pin1 binds to and isomerizes specific Ser(P)/Thr-Pro motifs and catalytically induces conformational changes after phosphorylation (7). Recently, Stanya et al. (8) showed ...

show abstract

Section: Discussionsupporting

confidence: 67%

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

Namgoong

Khanal

Cho

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A major endogenous regulator of autophagy is the kinase mTOR, and the disassembly of mTOR complexes TORC1 and TORC2 has been implicated in activation of autophagy (61). In our experiments, inhibition of mTORC1 by rapamycin elicited only modest effects on cell proliferation and on the sensitivity to combined treatment with (−)-gossypol and TMZ in U87 cells.…”

Section: Discussionmentioning

confidence: 54%

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Voss

Senft

Lang

et al. 2010

Molecular Cancer Research

172

145

View full text Add to dashboard Cite

Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O 6 -methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1.

show abstract

“…Emerging evidence suggests that all three MAPK subfamilies can regulate autophagy (30 -35). For example, several studies indicate that ERK promotes autophagy (34,35). In the case of JNK, it phosphorylates Bcl-2 upon starvation, thus disrupting Bcl-2/Beclin-1 binding and facilitating Beclin-1 interaction with Vps34 (33).…”

Section: Discussionmentioning

confidence: 99%

Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Wang

2014

Journal of Biological Chemistry

231

179

View full text Add to dashboard Cite

Background:The contribution of autophagy to acquired cisplatin resistance in ovarian cancer has not been studied. Results: Cisplatin treatment activates ERK and subsequently promotes autophagy and counteracts cisplatin-induced cell death. Inhibition of autophagy enhances cisplatin sensitivity. Conclusion: Cisplatin-induced autophagy contributes to cisplatin resistance. Significance: Targeting autophagy may overcome cisplatin resistance.

show abstract

A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1

Cited by 291 publications

References 62 publications

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Contact Info

Product

Resources

About