Glucose Oxidation Modulates Anoikis and Tumor Metastasis

Kamarajugadda, Sushama; Stemboroski, Lauren; Cai, Qingsong; Simpson, Nicholas E.; Nayak, Sushrusha; Tan, Ming; Lu, Jianrong

doi:10.1128/mcb.06248-11

Cited by 193 publications

(185 citation statements)

References 37 publications

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“…In lung cancer cells, inhibition of PDK4 promotes EMT associated with erlotinib resistance (50). On the other hand, PDK4 has been shown to contribute to anoikis resistance in cancer cells (51). A recent study reported that PDK4 promotes tumorigenesis through activation of the cAMP-response element-binding protein-ras homolog enriched in brain-mTORC1 signaling cascade (52).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGF␤ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGF␤ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGF␤ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGF␤/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.Colorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer mortality in the United States. In addition to surgery, treatment for colorectal cancer patients, especially for patients with advanced disease, primarily relies on chemotherapy and radiation therapy. 5 is one of the most commonly used chemotherapeutic agents for colorectal cancer treatment. It induces cell cycle arrest and apoptosis in cancer cells (1). Although adjuvant 5-FU treatment has a good success rate, the high recurrence is still a major hurdle of treating colorectal cancer because of the resistance to chemotherapeutic drugs. Therefore, it is important to understand the mechanisms of drug resistance and identify new targets to increase the effectiveness of chemotherapy in colorectal cancer. TGF␤ plays an important role in cancer development and progression. Upon ligand binding, TGF␤ type II receptor (RII) recruits and activates TGF␤ type I receptor (RI), which then activates Smad2 and Smad3. Activated Smad2 and Smad3 form complexes with Smad4 and translocate to the nucleus, where they regulate gene expression (2). We and others have demonstrated that TGF␤ suppresses tumorigenicity in a variety of cancers, including colorectal cancer, and that loss of TGF␤ signaling leads to malignancy (3-6). Although many studies have shown that TGF␤ promotes metastasis (7), others have demonstrated that TGF␤ suppresses metastasis (8,9). Recently, studi...

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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“…Consistent with these observations, some cancer cells undergo metabolic changes during invasion in vitro and metastasis in vivo that would be expected to reduce the generation of ROS (Chen et al 2007;Lu et al 2010;Qu et al 2011;Kamarajugadda et al 2012Kamarajugadda et al , 2013Dong et al 2013;Shi et al 2014). For example, HIF-1 activity is transiently increased during metastasis due to high ROS levels (Montagner et al 2012;Zhao et al 2014).…”

Section: Cancer Cells Undergo Metabolic Changes To Manage Rosmentioning

confidence: 61%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

229

164

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…Following reduced expression of E-cadherin, cancer cells are easily detached from the primary tumor to promote metastasis. However, detachment from the primary tumor also results in loss of interaction with the matrix and induction of anoikis, which is believed to act as a barrier to metastasis (45,46). Resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%