Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate

VanderWeele, David J.; Rudin, Charles M.

doi:10.1158/1541-7786.mcr-05-0063

Cited by 18 publications

(13 citation statements)

References 43 publications

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“…PI-3K, IKKα and NF-κB are known to contribute to tumor growth by promoting cell-cycle entry, cell proliferation, cell migration, or anti-apoptotic responses and are implicated in resistance to radio-and chemotherapy [39]. Activation of the PI3K/Akt pathway has been linked to chemotherapeutic resistance in human tumors [40], contributes to Cisplatin resistance in ovarian cancer cell lines [ 41 ] and to microtubule-directed agents including Vincristine in ovarian cancer [42]. Consequently, our observations that 7Me-IEITC inactivates the PI-3K pathway and downstream factors IKKα and NF-κB suggests that 7Me-IEITC could be used to enhance the effectiveness of chemotherapy in drug resistant cancers.…”

Section: Discussionmentioning

confidence: 99%

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

Singh¹,

Lange²,

Kim³

et al. 2008

Gynecologic Oncology

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Objective-A novel indole-ethyl isothiocyanate derivative (7Me-IEITC) was defined as a potent growth-suppressing agent to cell lines derived from ovarian cancers. Key mechanisms of the cellular response in vitro were studied and suggest a potential of 7Me-IEITC as a therapeutic drug.Methods-The viability of ovarian cancer cell lines (SKOV-3, OVCAR-3) in comparison to pancreatic and prostate cancer cell lines, primary fibroblast and immortalized trophoblasts after treatment with 7Me-IEITC was analyzed. Morphological and apoptotic responses of SKOV-3 were studied by fluorescence microscopy (DAPI staining, TUNEL assay). SKOV-3 proliferation was estimated by a standardized BrdU incorporation assay. The phosphorylation of MAP-Kinases, prosurvival factors and the activation of caspases and PARP-1 were analyzed by western blotting. Changes of the mitochondrial transmembrane-potential and in cell cycle progression were studied by FACS analysis. MAP-Kinase and caspase inhibitors were employed in cytotoxicity studies.Results-7Me-IEITC selectively reduced the viability of SKOV-3, OVCAR-3, BXPC-3 and PC-3 cells (IC50 values ≤5μM), while the viability of fibroblasts or trophoblasts remained unaffected at concentrations below 20μM. 7Me-IEITC treatment down-regulated pro-survival kinases and transcription factors (STAT-3, IKKα and NF-κB), caused rapid loss of the mitochondrial transmembrane-potential and inactivation of PARP-1 along with activation of caspases. The use of p38 MAP-Kinase-and caspase-inhibitors suppressed the cytotoxicity of the drug. 7Me-IEITC acted as an anti-proliferative agent and arrested the cell-cycle progression of SKOV-3 in G2/M phase.Conclusion-7Me-IEITC is a potent and growth-suppressing agent to cell lines derived from ovarian cancers by causing de-activation of survival signals, apoptosis, and cell-cycle arrest.

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Section: Discussionmentioning

confidence: 99%

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

Singh¹,

Lange²,

Kim³

et al. 2008

Gynecologic Oncology

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“…For example, a constitutionally active AKT (Brognard et al, 2001; Clark et al, 2002; Vivanco and Sawyers, 2002) or chemotherapy-induced activation of AKT may render tumors resistant to anticancer therapies (Chakravarti et al, 2002; VanderWeele et al, 2004; VanderWeele and Rudin, 2005; Bozulic et al, 2008; Hurvitz et al, 2013). In breast cancer, a hyperactive AKT mediated by PTEN loss, PIK3CA, or AKT mutations resulted in resistance to anti-HER2 antibody, trastuzumab (Hurvitz et al, 2013).…”

Section: Role Of Mtor In Tumorigenesis and Chemoresistancementioning

confidence: 99%

“…In glioblastoma treated with epidermal growth factor receptor inhibitors, drug resistance was mediated via amplification of AKT activity following a compensatory increase in insulin growth factor receptor signaling (Chakravarti et al, 2002). AKT have also been reported to mediate chemoresistance to microtubule inhibitors including vincristine and paclitaxel as well as topoisomerase II inhibitor such as doxorubicin (VanderWeele et al, 2004; VanderWeele and Rudin, 2005; Bozulic et al, 2008). The drug resistance propagated through AKT in turn have been shown to be dependent on mTOR signaling (VanderWeele et al, 2004; Wendel et al, 2004; VanderWeele and Rudin, 2005).…”

Section: Role Of Mtor In Tumorigenesis and Chemoresistancementioning

confidence: 99%

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

et al. 2016

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The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.

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“…Glycolysis rates were measured by following the conversion of 5-3 H-glucose to 3 H 2 O as described previously (19). Briefly, cells were washed once in PBS before incubation in Krebs buffer without glucose for 30 min at 37˚C.…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect

et al. 2012

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Abstract. Colorectal cancer represents one of the most challenging diseases. Increasing evidence indicates that aberrant expression of microRNAs (miRNAs) is related to pathogenesis of colorectal cancer. Cancer cells reprogram metabolic pathways to sustain higher proliferation rates. Whether mechanisms underlying the role of miRNA in colorectal cancer are involved in metabolic reprogramming and the mechanisms through which miRNAs alter cancer metabolism are as yet unknown. Herein, we show that miR-124, miR-137 and miR-340 are associated with poor prognosis of colorectal cancer. Expression of these miRNAs inhibits the growth of colorectal cancer cells. PKM (pyruvate kinase isozyme) alternative splicing proteins (PTB1/ hnRNAPA1/hnRNAPA2), which control the inclusion of exon 9 (PKM1) or exon 10 (PKM2), are targeted by miR-124, miR-137 and miR-340. Consequently, miR-124, miR-137 and miR-340 switch PKM gene expression from PKM2 to PKM1. High ratios of PKM1/PKM2 inhibit the glycolysis rate, but elevate the glucose flux into oxidative phosphorylation. These results demonstrate that miRNAs (miR-124, miR-137 and miR-340) impair colorectal cancer growth by counteracting the Warburg effect due to regulating alternative splicing of the PKM gene. IntroductionColorectal cancer (CRC) is the third most common type of cancer. About 608,700 deaths from CRC occurred in 2008, accounting for 8% of all cancer deaths (1). About 30% of recurrent CRC patients have liver metastasis, and >70% of them are not candidates for curative resection (2). In the past few years, accumulating evidence has suggested that microRNAs (miRNAs) are involved in the pathogenesis of CRC (3). The pattern of miRNA expression is related with cancer type, stage and other clinical variables, which makes miRNA a promising prognostic and therapeutic tool (4,5).In order to support high rates of proliferation, cancer cells consume additional nutrients and divert those nutrients into macromolecular synthesis pathways. Cancer cells prefer to metabolize glucose by glycolysis, intentionally avoid oxidative phosphorylation even when oxygen is abundant -the Warburg effect (6). Therefore, many cancer cells are characterized with increased lactate production and decreased O 2 consumption (7). Active glycolysis coupled with increased glucose intake will provide sufficient intermediate metabolites, such as NADPH, acetyl-CoA and ribose, for biosynthetic process (8,9).Pyruvate kinase (PK), which converts phosphoenolpyruvate into pyruvate, is one of rate-limiting enzymes in glycolytic pathway. PKM is alternatively spliced to either M1 (PKM1) or M2 (PKM2) isoform, which contains exon 9 or exon 10, respectively (10,11). The single exon difference endows the enzymes with distinct expression patterns and functions. PKM2 is exclusively expressed in embryonic, proliferating and cancer cells, which promotes glycolysis even in an aerobic environment. PKM1 is expressed in normal differentiated tissues, which promotes oxidative phosphorylation (12,13). The expression PKM2 is critical for ca...

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Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate

Cited by 18 publications

References 43 publications

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect

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