Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha- RAS -transformed human colon cells

Psahoulia, Faiy H.; Moumtzi, Sophy; Roberts, Michael L.; Sasazuki, Takehiko; Shirasawa, Senji; Pintzas, Alexander

doi:10.1093/carcin/bgl232

Cited by 117 publications

(66 citation statements)

References 34 publications

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“…We observed that when RAS induced small increases in autophagic activity, this was accompanied by senescence in ASPP2 WT MEFs. In ASPP2 (Δ3/Δ3) MEFs, however, RAS-induced autophagic activity was over twofold higher than that observed in RAS-expressing ASPP2 WT MEFs, illustrating how ASPP2's status may explain why HRAS V12 induces autophagy in some cells and fails to do so in others (9,27). The observed large increase in autophagic activity in HRAS V12-expressing ASPP2 (Δ3/Δ3) MEFs was the result of a significant increase in ATG5/ATG12 expression, and this increase was most profound in HRAS V12-expressing ASPP2 (Δ3/Δ3) MEFs that escaped senescence.…”

Section: Discussionmentioning

confidence: 96%

Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

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

109

124

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RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2 (Δ3/Δ3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.A ctive mutations of RAS, one of the first oncogenes identified, occur in about 20% of human tumors (1). Oncogenic RAS can transform cells and promote tumorigenesis, although it can also induce senescence and suppress tumor growth (2). Senescent cells are arrested and incapable of responding to mitogens, although they are viable and metabolically active. Senescence is characterized by dramatic cellular remodelling, which is energetically demanding. Autophagy, a genetically regulated process responsible for the turnover of cellular proteins and damaged or superfluous organelles, is a stress response involved in energy homeostasis (3). It was shown that autophagy is a critical mediator of oncogenic RAS-induced senescence, suggesting a negative role of autophagy in tumorigenesis (4). In contrast, a number of recent studies showed that active RAS requires autophagy to maintain its oncogenic function in tumorigenesis, arguing for a positive role of autophagy in tumorigenesis (5-8). The underlying reason for the conflicting observations remains unclear.RAS activation inhibits autophagy by activating the PI3K/ AKT/mammalian target of rapamycin (mTOR) pathway (9), and rapamycin, an mTOR inhibitor, is a potent inducer of autophagy. RAS also inhibits autophagy by reducing Beclin-1 expression in intestinal epithelial cells, an important mediator of autophagy (10). However, RAS was reported to induce autophagy by increasing the expression of key components of the autophagy machinery, such as ATG5 (11) and Beclin-1 (12). These reports suggest that RAS signaling performs a finely regulated balancing act to control autophagy. Identification of switching molecules that determine the cellular responses to RAS is thus needed urgently.The tumor suppressor p53 is one of the most well-established pathways by which RAS mediates cellular senescence. A recent study also showed that p53 is able to regulate autophagic activity by inducing the expression of LC3 (13). However, it remains unknown whether the abilit...

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Section: Discussionmentioning

confidence: 96%

Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

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

109

124

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“…Likewise, prenylflavonoids from hop (Humulus lupulus L.) at doses of 100 to 200 Amol/L induced autophagic cell death in human prostate cancer cells (164).The food polyphenol quercetin was shown to induce apoptosis and, at a dose of 20 Amol/L, to stimulate autophagic vacuolization specifically in Ha-Ras -transformed human Caco2 colon cancer cells. Quercetin also suppressed cell viability and anchorage-independent growth (165). In contrast, Caco2 cells with wild-type Ras or transformed with Ki-Ras resisted quercetin-induced autophagic vacuolization.…”

Section: Such Findings Have Sparked Interest In Exploring the Importamentioning

confidence: 93%

Diet, Autophagy, and Cancer: A Review

Singletary

Milner

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

146

102

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A host of dietary factors can influence various cellular processes and thereby potentially influence overall cancer risk and tumor behavior. In many cases, these factors suppress cancer by stimulating programmed cell death. However, death not only can follow the well-characterized type I apoptotic pathway but also can proceed by nonapoptotic modes such as type II (macroautophagy-related) and type III (necrosis) or combinations thereof. In contrast to apoptosis, the induction of macroautophagy may contribute to either the survival or death of cells in response to a stressor. This review highlights current knowledge and gaps in our understanding of the interactions among bioactive food constituents, autophagy, and cancer. Whereas a variety of food components including vitamin D, selenium, curcumin, resveratrol, and genistein have been shown to stimulate autophagy vacuolization, it is often difficult to determine if this is a protumorigenic or antitumorigenic response. Additional studies are needed to examine dose and duration of exposures and tissue specificity in response to bioactive food components in transgenic and knockout models to resolve the physiologic implications of early changes in the autophagy process. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1596 -610)

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“…Interestingly, treatment of human HCT15 colon adenocarcinoma culture cells with Bgroup soyasa ponins induced autophagy and suppressed prolifer ation through a marked increase in autophagic cell death [129] . In addition to its effects on cell viability and anchorageindependent growth inhibition, the flavonoid quercetin induced autophagic processes in HaRas transformed human colon cells and has been proposed to have anticancer properties [130] . Vitamin D can trigger autophagy by enhancing BECN1 expression and inducing PI3KC3 expression [131] .…”

Section: Autophagy Drugs In Crcmentioning

confidence: 99%

Autophagy in colorectal cancer: An important switch from physiology to pathology

Burada

Nicoli

Ciurea

et al. 2015

WJGO

137

131

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Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of Core tip: This review describes the role of autophagy in cancer, focusing on the involvement of autophagy in colorectal cancer (CRC). Initially, we describe the steps and components of autophagy, and we then further highlight the dual role of autophagy in cancer, where it can potentially act as both a promoter and an inhibitor during the transformation from normal to malignant cell. In particular, we emphasize the major autophagy genes involved in CRC pathogenesis along with autophagymodulating agents and their modes of action in the context of CRC therapy. TOPIC HIGHLIGHT

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Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha- RAS -transformed human colon cells

Cited by 117 publications

References 34 publications

Autophagic activity dictates the cellular response to oncogenic RAS

Autophagic activity dictates the cellular response to oncogenic RAS

Diet, Autophagy, and Cancer: A Review

Autophagy in colorectal cancer: An important switch from physiology to pathology

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