Broad Phenotypic Changes Associated with Gain of Radiation Resistance in Head and Neck Squamous Cell Cancer

Bansal, Nidhi; Mims, Jade; Kuremsky, Jeffrey G.; Olex, Amy L.; Zhao, Weiling; Yin, Lei‐Miao; Wani, Revati; Qian, Jiang; Center, Brian; Marrs, Glen S.; Porosnicu, Mercedes; Fetrow, Jacquelyn S.; Tsang, Allen W.; Furdui, Cristina M.

doi:10.1089/ars.2013.5690

Cited by 36 publications

(80 citation statements)

References 49 publications

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“…2C). These results are also consistent with the functional analysis of our previously published quantitative proteomic data for SCC-61 and rSCC-61 cells, which showed significantly increased nucleotide metabolism, DNA replication and base excision repair in rSCC-61 (24). …”

Section: Resultssupporting

confidence: 92%

“…2A). In addition, quantitative proteomics analysis reported earlier showed a 3.5-fold increased expression in rSCC-61 of the enzyme 6-phosphogluconate dehydrogenase (6PGD) catalyzing the second NADPH producing step in the oxidative phase of PPP (24). Based on these results, we hypothesized that rSCC-61 would be more dependent on PPP than SCC-61.…”

Section: Resultsmentioning

confidence: 93%

“…1 and 2 demonstrate an increased dependence on overall glucose metabolism in rSCC-61 cells and increased flux through PPP in these cells. We have reported previously that rSCC-61 cells have increased expression of lactate dehydrogenase B enzyme (favoring conversion of lactate to pyruvate) and decreased expression of lactate dehydrogenase A (favoring conversion of pyruvate to lactate) (24), which also pointed to a possible diversion from the conventional Warburg metabolism. Taken together, the data indicated that a significant proportion of glycolytic flux was diverted into lactic acid synthesis in SCC-61 while in rSCC-61 the upstream glycolytic intermediates were funneled into the PPP but also possibly into the TCA and mitochondrial electron transfer chain (ETC) to support OXPHOS.…”

Section: Resultsmentioning

confidence: 96%

“…The generation of the SCC-61/rSCC-61 matched model of response to radiation was described earlier (24). Briefly, the radiation-sensitive SCC-61 cells were irradiated in vitro with fractionated ionizing radiation (8 × 2 Gy), the resulting cell population was plated on soft agar and a single colony (rSCC-61) was picked for in-depth analysis of the mechanisms driving the response to radiation treatment in HNSCC.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, a better understanding of the underlying molecular and metabolic regulation that leads to radiation-resistant cells in HNSCC could significantly aid in the introduction of more effective and novel therapeutics. In an effort to underpin the molecular reprogramming associated with the acquisition of radiation resistance in HNSCC, we developed a matched model of radiation-resistant cells for this disease, the SCC-61/rSCC-61 system, which we reported on previously (24). Quantitative proteomic profiling showed broad changes in protein expression in the radioresistant cells (rSCC-61) that were associated with cellular metabolism, in addition to the expected upregulation of proteins involved in protection against DNA damage (24).…”

Section: Introductionmentioning

confidence: 99%

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Energy Metabolism in a Matched Model of Radiation Resistance for Head and Neck Squamous Cell Cancer

et al. 2015

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While radiation therapy is commonly used for treating cancer, radiation resistance can limit long-term control of the disease. In this study, we investigated the reprogramming of the energy metabolism in radiosensitive and radioresistant head and neck squamous cell carcinomas (HNSCC) using a preclinical matched model of radiation resistance. Our investigation found that radioresistant rSCC-61 cells: 1. They display increased glucose uptake and decreased fatty acid uptake; 2. They deviate from the classical Warburg effect by diverting the glycolytic flux into the pentose phosphate pathway; 3. They are more dependent on glucose than glutamine metabolism to support growth; 4. They have decreased mitochondrial oxidative phosphorylation; 5. They have enhanced fatty acid biosynthesis by increasing the expression of fatty acid synthase; and 6. They utilize endogenous fatty acids to meet the energy demands for proliferation. Inhibition of fatty acid synthase with orlistat or FASN siRNA resulted in increased cytotoxicity and sensitivity to radiation in rSCC-61 cells. These results demonstrate the potential of combination therapy using radiation and orlistat or other inhibitors of lipid and energy metabolism for treating radiation resistance in HNSCC.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Energy Metabolism in a Matched Model of Radiation Resistance for Head and Neck Squamous Cell Cancer

et al. 2015

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High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

et al. 2022

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Different from conventional vaccines, in situ vaccination could conveniently convert established tumors into a "vaccine factory" to release various tumor antigens for stimulating and diversifying antitumor T-cell response. [3] Radiation therapy (RT) is a widely used local therapy of malignancies and exhibits great potential in inducing in situ tumor vaccine effect. [4] However, even potentiated by CBI, RT could only lead to mild to moderate immune response within nonirradiated tumors, which is far less than medical needs. [5] Therefore, it is quite meaningful to boost RT-mediated in situ vaccination to extend its therapeutic effect to the whole body.To achieve this goal, a possible way could be potentiating RT-induced immunogenic cell death (ICD). ICD is a death modality accompanied by releasing tumor antigens and damage-associated molecular patterns, including calreticulin (CRT), high mobility group protein B1 (HMGB1), etc., which could provide antigens and adjuvants for tumor vaccination. [6] Currently, some studies have indicated that oxidative stress and DNA damage within tumor cells could potentially result in ICD. [7] However, due to the insufficient deposition of X-ray within tumor tissues, only low level of reactive oxygen species (ROS) could be produced to induce oxidative stress upon the recommended radiation doses. To address this problem, radiosensitizers based on high-Z elements are being developed widely to deposit X-ray for amplifying RT-induced oxidative stress. Of note, HfO 2 nanoparticles (Hensify) have been approved in Europe for locally advanced soft tissue sarcoma treatment [8] and are confirmed to augment RT-mediated antitumor immunity effect in many clinical trials. However, their slight improvements suggest the room for optimization. [9] The pentose phosphate pathway (PPP) is a branch of glycolysis and hyperactive in most tumors, [10] which could provide abundant NADPH and ribose 5-phosphate to maintain redox and nucleotides homeostasis, respectively. [11] NADPH is a central player in cellular antioxidant system, which not only mediates GSH synthesis, [12] but also acts as an electron donor to reduce oxidized GSH and thioredoxin (Trx, an important In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide...

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Metabolic response to radiation therapy in cancer

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Vlashi

et al. 2021

Molecular Carcinogenesis

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Tumor metabolism has emerged as a hallmark of cancer and is involved in carcinogenesis and tumor growth. Reprogramming of tumor metabolism is necessary for cancer cells to sustain high proliferation rates and enhanced demands for nutrients. Recent studies suggest that metabolic plasticity in cancer cells can decrease the efficacy of anticancer therapies by enhancing antioxidant defenses and DNA repair mechanisms. Studying radiation‐induced metabolic changes will lead to a better understanding of radiation response mechanisms as well as the identification of new therapeutic targets, but there are few robust studies characterizing the metabolic changes induced by radiation therapy in cancer. In this review, we will highlight studies that provide information on the metabolic changes induced by radiation and oxidative stress in cancer cells and the associated underlying mechanisms.

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Broad Phenotypic Changes Associated with Gain of Radiation Resistance in Head and Neck Squamous Cell Cancer

Abstract: The rSCC-61/SCC-61 model provides the opportunity for future investigations of the redox-regulated mechanisms of response to combined radiation and Erlotinib in a preclinical setting.

Cited by 36 publications

References 49 publications

Energy Metabolism in a Matched Model of Radiation Resistance for Head and Neck Squamous Cell Cancer

Energy Metabolism in a Matched Model of Radiation Resistance for Head and Neck Squamous Cell Cancer

High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

Metabolic response to radiation therapy in cancer

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