Apoptosis induced by PGC-1β in breast cancer cells is mediated by the mTOR pathway

Wang, Yunlong; Liu, Qilun; Li, Fang; Qiu, Jing; Fan, Huishou; Ma, Hongwei; Zhu, Yuyan; Wu, Ligang; Han, Xiao; Yang, Zhihong; Jiang, Hua; Wei, Jun; Xia, Haibin

doi:10.3892/or.2013.2628

Cited by 12 publications

(14 citation statements)

References 38 publications

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“…However, a recent study suggested that long-term PGC1β overexpression could lead to apoptosis, autophagy, and atrophy in the skeletal muscle of mice (43). Additionally, it has been suggested that PGC1β overexpression decreases apoptosis in breast cancer cells (44). In our study, we noticed a dynamic change of either miR-378 or PGC1β mRNA expression on metabolic stress ( Fig.…”

Section: Discussionmentioning

confidence: 43%

microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

Jiang

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

106

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The metabolic regulation of cell death is sophisticated. A growing body of evidence suggests the existence of multiple metabolic checkpoints that dictate cell fate in response to metabolic fluctuations. However, whether microRNAs (miRNAs) are able to respond to metabolic stress, reset the threshold of cell death, and attempt to reestablish homeostasis is largely unknown. Here, we show that miR-378/378* KO mice cannot maintain normal muscle weight and have poor running performance, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis in skeletal muscle, whereas miR-378 overexpression is able to enhance autophagy and repress apoptosis in skeletal muscle of mice. Our in vitro data show that metabolic stress-responsive miR-378 promotes autophagy and inhibits apoptosis in a cell-autonomous manner. Mechanistically, miR-378 promotes autophagy initiation through the mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase 1 (ULK1) pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1). Meanwhile, miR-378 suppresses intrinsic apoptosis initiation directly through targeting an initiator caspase—Caspase 9. Thus, we propose that miR-378 is a critical component of metabolic checkpoints, which integrates metabolic information into an adaptive response to reduce the propensity of myocytes to undergo apoptosis by enhancing the autophagic process and blocking apoptotic initiation. Lastly, our data suggest that inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy.

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Section: Discussionmentioning

confidence: 43%

microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

Jiang

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Furthermore, suppressing PGC1␤ and ERR␣ expression decreased colon tumor cell viability and anchorage-independent growth and delayed tumor formation in nude mice, making them potential targets in cancer therapy. PGC1␤ and ERR␣ have been studied extensively as metabolic regulators that promote tumorigenesis in breast cancer (45)(46)(47)(48)(49). Breast cancer has a low incidence of activating Ras mutations but are often driven by the overexpression of ERBB2, which signals through Ras (50).…”

Section: Discussionmentioning

confidence: 99%

AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

Fisher

Das

Kim

et al. 2015

Molecular and Cellular Biology

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A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferatoractivated receptor gamma coactivator 1␤ (PGC1␤) and estrogen-related receptor ␣ (ERR␣) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the ␥1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1␤ expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (␣2␤2␥1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1␤. In contrast, PGC1␤ and ERR␣ are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPK␥1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1␤-dependent transcriptional pathway via a specific AMPK isoform.A third of all human cancers, including a substantial percentage of colorectal, lung, and pancreatic cancers, are driven by activating mutations in Ras genes. Activating K-Ras mutations are present in 35 to 40% of colon tumors and are thought to be both drivers of tumorigenesis and determinants of therapeutic regimens (1). Therapeutic disruption of Ras function has been clinically ineffective to date, but investigation of Ras pleiotropy continues to yield a diversity of downstream effectors with obligate roles in the maintenance and adaptation of Ras-driven tumors to changing environments. The Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway is essential for the oncogenic properties of mutated K-Ras (2). However, numerous potent and specific MEK inhibitors have been developed yet have failed to demonstrate single-agent efficacy in cancer treatment (3). As a molecular scaffold of the Raf-MEK-ERK kinase cascade (4, 5), kinase suppressor of Ras 1 (KSR1) is necessary and sufficient for Ras V12 -induced tumorigenesis (4), mouse embryo fibroblast (MEF) transformation (5, 6), and pancreatic cancer growth (7) but dispensable for normal development (4). KSR1 is overexpressed in endometrial carcinoma and is required for both proliferation and anchorage-independent growth of endometrial cancer cells (8). Except for minor defects in hair follicles, KSR1 knockout mice are fertile and develop normally (4).This observation predicts that small molecules targeting KSR1 and functionally related effectors should preferentially target Rasdriven tumors while leaving normal tissue largely unaffected. More generally, this observation demonstrates that tumor cells, while under selective pressure to adapt to inhospitable environments and proliferate without constraint, will adopt strategies that, while advantageous to that singular purpose, create...

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“…It was shown that the levels of PGC-1β and mTOR correlated with overall mitochondrial activity in breast cancer samples. Moreover, the knockdown of endogenous PGC-1β, leads to a decreased expression of mTOR pathway related genes and induces apoptosis in MDA-MB-231 cells (143). Interestingly, it was demonstrated that the branched chain amino acid transaminase 1 (BCAT1) actives mTORC1 and in consequence promotes the mitochondrial biogenesis, ATP production and defense of oxidative stress (143).…”

Section: Mitochondrial Biogenesis and Mitophagy: Mtorc1 In Cancermentioning

confidence: 99%

“…Moreover, the knockdown of endogenous PGC-1β, leads to a decreased expression of mTOR pathway related genes and induces apoptosis in MDA-MB-231 cells (143). Interestingly, it was demonstrated that the branched chain amino acid transaminase 1 (BCAT1) actives mTORC1 and in consequence promotes the mitochondrial biogenesis, ATP production and defense of oxidative stress (143). The inhibition of mTORC1 with rapamycin, neutralized the roles of BCAT1 in mitochondrial function and breast cancer cell growth (143).…”

Section: Mitochondrial Biogenesis and Mitophagy: Mtorc1 In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Apoptosis induced by PGC-1β in breast cancer cells is mediated by the mTOR pathway

Cited by 12 publications

References 38 publications

microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

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