Cancer Notes

This post was written by marc on September 22, 2016
Posted Under: Letters to the Editor

Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells

Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities.

The goals of this study were to determine whether oncogenic RETregulates mTOR activity in MTC and PTC cells and whether targeted inhibition of these two kinases shows cooperative effects on growth suppression. mTOR activity was exquisitely RET-dependent in all cell lines tested. Treatment of RET mutant thyroid cancer cell lines with the RET kinase inhibitor NVP-AST487 profoundly inhibited their growth. Similar effects were noted when these cells were treated with the mTOR kinase inhibitor INK128. However, their combination at high concentrations showed no additive effect, pointing to a possible common mechanism of action. Indeed, when combined at lower concentrations, the RET and mTOR kinase inhibitors showed strong cooperativity. These results indicate a critical role of mTOR signaling in RET-induced cell growth and provide strategies to maximize therapeutic effects when toxicity precludes using RET kinase inhibitors at their maximally effective dose.

Pterostilbene inhibits lung cancer through induction of apoptosis.

Lung cancer remains the leading cause of cancer mortality in the United States. Resveratrol is a potent antioxidant found in grapes that inhibits several types of cancer, including lung cancer. Herein, we investigated the effects of pterostilbene, an analog of resveratrol found in blueberries, on lung cancer, in vitro. We hypothesized that pterostilbene would inhibit lung cancer cell growth in vitro by a pro-apoptotic mechanism.


Two lung cancer cell lines (NCI-H460 and SK-MES-1) were cultured using standard techniques. Cells were treated with increasing doses of pterostilbene (10-100 microM). Cell viability was measured at 24, 48, and 72h using a MTT assay. Apo-ONE Caspase-3/7 assay was used to evaluate caspase activity. T-test and two-way ANOVA were used for statistical analysis.


Pterostilbene significantly decreased cell viability in lung cancer cells in a concentration- and time-dependent manner (P<0.001). Concentrations greater than 20 microM of pterostilbene produced significant growth inhibition by 72h (P<0.001). Apoptosis and caspase-3/7 activity were significantly increased by pterostilbene treatment (P<0.05).


Pterostilbene inhibits growth via apoptosis induction in vitro. Further in vitro mechanistic studies and in vivo experiments are warranted to determine the potential role for pterostilbene in lung cancer treatment or prevention.


Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells

A Combination of Pterostilbene With Autophagy Inhibitors Exerts Efficient Apoptotic Characteristics in Both Chemosensitive and Chemoresistant Lung Cancer Cells


Geroncogenesis: Metabolic Changes during Aging as a Driver of Tumorigenesis

Sirtuins Are Central to Metabolic Reprogramming during Aging and Cancer

Table 1

Evidence for Sirtuins as Tumor Suppressors or Promoters

Another sirtuin implicated in tumorigenesis is SIRT6, a chromatin-associated enzyme with deacetylase and long-chain deacylase activities.Sirt6 deletion increases HIF-1α and c-Myc transcriptional activity, with a corresponding upregulation of glycolysis (Sebastián et al., 2012;Zhong et al., 2010). Remarkably, knockdown of Sirt6 in otherwise normal mouse embryonic fibroblasts (MEFs) transforms them, independently of activation of known oncogenes (Sebastián et al., 2012). Although SIRT6 is required for genomic stability (Mostoslavsky et al., 2006), re-introduction of Sirt6 into knockout MEF cells in which genomic instability might already have been expected to take place represses tumor formation, effectively ruling out mutations as a cause (Sebastián et al., 2012). These findings further underscore the idea that metabolic alterations are required, if not sufficient, to induce tumor growth.

SIRT1, a nuclear sirtuin, was the first family member shown to act as a tumor suppressor. Pharmacological activation or genetic overexpression of Sirt1 increases genomic stability in cells treated with DNA-damaging agents, delays lymphoma, and improves the survival of irradiated p53+/−mice (Oberdoerffer et al., 2008), while Sirt1 deletion has the opposite effect (Wang et al., 2008). By localizing to sites of DNA damage and facilitating the recruitment of DNA repair factors such as histone deacetylase 1, Rad51, and Nbs1, SIRT1 plays a key role in promoting genome stability, a function that declines with age (Dobbin et al., 2013;Oberdoerffer et al., 2008). One of the strongest effects of SIRT1 in vivo is its ability to protect mice in the heterogeneous diethylnitrosamine-induced model of hepatocellular carcinoma (Herranz et al., 2010), potentially by suppressing inflammatory responses in this organ. SIRT1 can also suppress tumorigenesis by negatively regulating oncogenic transcription factors, including β-catenin (Firestein et al., 2008) and c-Myc (Yuan et al., 2009), though opposing findings for Myc have been reported (Menssen et al., 2012).

Similar to SIRT3 and SIRT6, SIRT1 might influence tumorigenesis, not only through its ability to regulate genomic stability, but also by regulating cellular metabolism. SIRT1 regulates the transcriptional activity of HIF-1α (Lim et al., 2010), which is also an important regulator of the Warburg effect as well as angiogenesis and metastasis. SIRT1 also deacetylates and activates liver kinase B1 (LKB1; Lan et al., 2008), a known tumor suppressor that regulates mTOR and AMPK (Sedelnikova et al., 2004). Interestingly, the effects of SIRT1 on tumorigenesis are context dependent. For example, inhibition of SIRT1 improves the efficacy of a chemotherapeutic agent (Imatinib) against chronic myeloid leukemia (Li et al., 2012) and blocks the proliferation of hepatocellular carcinoma cell lines in vitro and in a xenograft model (Portmann et al., 2013). Conversely, Sirt1 overexpression can accelerate thyroid cancers in vivo (Herranz et al., 2013). These latter findings likely reflect the ability of SIRT1 to inhibit the tumor suppressor p53, which promotes survival under situations of cell stress (Luo et al., 2001).

There is evidence that SIRT2, the cytosolic sirtuin, is also a tumor suppressor. Deletion of Sirt2 results in spontaneous tumorigenesis in the liver and accelerates the 7,12-dimethyl-benz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate model of skin cancer (Narayan et al., 2012; Serrano et al., 2013). One mechanism is likely to be cell cycle control, as SIRT2 deacetylates and regulates CDH1 and CDC20, members of the anaphase-promoting complex (Narayan et al., 2012). Moreover, SIRT2 transiently migrates to the nucleus during mitosis (North and Verdin, 2007), where it modulates the activity of the methyltransferase PR-Set7, resulting in H4K20 methylation (Serrano et al., 2013), a chromatin mark involved in genomic stability (Oda et al., 2009). Although primarily studied in the context of its cytosolic regulation of cell cycle, one interesting possibility is that SIRT2 influences mitochondrial function and the Warburg effect by deacetylating CDH1, a protein that limits glycolysis and proliferation of cancer cell lines through ubiquitination and degradation of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase (Almeida et al., 2010). Again, the data are not clear cut; an in vitro study found that SIRT2 knockdown or small molecule inhibition reduced neuroblastoma cell growth through stabilization of Myc oncoproteins (Liu et al., 2013).

Recently, two other sirtuins, SIRT4 and SIRT7, have also been implicated in the regulation of tumorigenesis. The mitochondrial sirtuin SIRT4 promotes metabolic reprogramming by facilitating the cataplerotic diversion of carbons from the TCA cycle to aerobic glycolysis and lactate generation, forcing cancer cells to rely on glutamine for replenishment of the TCA cycle (Csibi et al., 2013; Jeong et al., 2013). Upon DNA damage, Sirt4 expression is upregulated, leading to a repression of glutamine metabolism through its inhibition of glutamate dehydrogenase, which converts glutamate into α-ketoglutarate (Csibi et al., 2013; Jeong et al., 2013). This shift prevents the cell from upregulating nonessential biosynthetic pathways and undergoing premature cellular division prior to genomic repair (Csibi et al., 2013;Jeong et al., 2013). The nucleolar sirtuin, SIRT7, may also regulate cellular metabolism by negatively regulating HIF-1α and HIF-2α (Hubbi et al., 2013), potentially underlying the Warburg effect. The role of SIRT7 in tumorigenesis, however, also seems context dependent: SIRT7 may help maintain a pro-oncogenic phenotype by interacting with the transcription factor ELK4 and deacetylating H3-K18, a modification that promotes tumor growth (Barber et al., 2012).

Beyond Resveratrol: The Anti-Aging NAD Fad

NAD+ and SIRT1: Their Role In Chronic Health Issues


NAD+ and SIRT1: Their Role In Chronic Health Issues


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