統計資料顯示，約 50~80%癌症病患會發生癌症惡病質，且約20%癌症病 患會因癌症惡病質相關併發症而死亡。癌症惡病質誘發的骨骼肌肉耗損會降低癌症病患 對治療的耐受性及存活率。癌細胞分泌的促蛋白質異化物質及誘發大量促發炎細胞激素 分泌可降低肌肉蛋白質合成及增加蛋白質降解是造成癌症惡病質病患骨骼肌肉耗損的 主因。癌症惡病質病患及癌症惡病質鼠類皆發骨骼肌蛋白質合成減少與經泛素-蛋白酶 體途徑 (ubiquitin-proteasome pathway, UPP)和自噬作用-溶酶體途徑 (autophagy-lysosome pathway, ALP)的蛋白質降解增加。癌細胞分泌物經由誘發轉錄因子 nuclear factor-B (NF-B), the forkhead type transcription factors (FoxOs),及 CCAAT/enhancer binding protein (C/EBP)的轉錄活性，增加UPP 及ALP 路徑中與肌 肉蛋白質降解相關atrophy-specific genes (統稱為atrogenes)蛋白質表現量，導致骨骼肌肉 耗損。Gamma 次亞麻油酸 (gamma linolenic acid, GLA)，雖可經由6 desaturase 代謝亞 麻油酸 (linoleic acid, LA)生成，但許多生理及病理因素會降低6 desaturase 酵素活性， 導致體內無法自行合成GLA，需由飲食中補充，故GLA 被認為是條件必需脂肪酸 (conditional essential fatty acid)。研究證實GLA 優於LA，具有抗發炎的及抑制 lipopolysaccharide 誘發C2C12 骨骼肌纖維細胞及C57BL/6 小鼠骨骼肌耗損的功效。本 計畫將以癌症惡病質小鼠及含癌細胞培養基的Conditioned media 及TNF- 處理已分化 的C2C12 骨骼肌纖維細胞為研究模式，探討GLA 調控癌症惡病質誘發骨骼肌肉耗損之 功效及相關機制。本計畫假說，GLA 可經由抑制癌細胞誘發骨骼肌轉錄因子NF-B， FoxOs 及C/EBP 轉錄活性，抑制UPP 及ALP 相關atrogenes 表現，而減緩骨骼肌肉蛋 白質降解及增加蛋白質合成，且GLA 調控癌症惡病質肌肉耗損的功效優於LA。本研究 計畫結果有助於了解GLA 對抑制癌症惡病質誘發骨骼肌肉耗損的保健功效，並提供了 解飲食中添加富含GLA 油脂作為改善癌症惡病質病患肌肉耗損輔助治療的可行性，以 作為研發富含GLA 相關保健食品的參考依據。 Among cancer patients, approximately 50 to 80 % are affected by cachexia, and 20% die as a result. Cancer cachexia induced depletion of skeletal muscle will reduce tolerance to the treatment and survival rate of cancer patients. That cancer cells secreted proteolysis factor and induced pro-inflammatory cytokine production could reduce muscle protein synthesis and increase protein degradation of cancer patients. Both cancer cachexia patients and rodents with cancer cachexia have shown decreasing skeletal muscle protein synthesis and increasing skeletal muscle protein breakdown through ubiquitin-proteasome pathway (UPP) and autophagy-lysosomal pathway (ALP). Cancer cells through acivitation of transcription factors such ase nuclear factor-B (NF-B), the forkhead type transcription factors (FoxOs), and CCAAT/enhancer binding protein (C/EBP) increased UPP and ALP related atrophy-specific gene expression which results in skeletal muscle wasting. Although gamma linolenic acid (GLA) can be generated via the metabolism of linoleic acid (LA) catalyzed by 6 desaturase, many physiological and pathological factors will reduce 6 desaturase enzyme activity. In these situations body could not synthesize GLA and needs to be supplemented by the diet, so GLA is considered as conditional essential fatty acids. Study confirmed that GLA superior LA has anti-inflammation and inhibition of lipopolysaccharide-induced skeletal muscle depletion in C2C12 myotubes and C57BL/6 mice. This project will explore the effect of GLA on cancer cachexia-induced skeletal muscle wasting by using C2C12 myotubes and cancer cachexia mouse models. The hypothesis of this project is that GLA through inhibiting transcriptional activity of NF-B, FoxOs and C/EBP decreased cancer cachexia induced expression of UPP and ALP related atrogenes, which diminished cancer cachexia induced decreasing protein synthesis and increasing protein degradation of skeletal muscle. Moreover, the inhibitory effect of GLA is better than LA. The results of this research project will help to understand the health benefits of GLA on inhibiting cancer cachexia-induced skeletal muscle wasting. Moreover, these data will help to understand the effect of enriching GLA containing oil on cancer cachexia patents with skeletal muscle wasting and provide the idea to study the health benefits of GLA functional foods.
