Patient-Derived Pancreatic Cancer Cells Induce C2C12 Myotube Atrophy by Releasing Hsp70 and Hsp90.
Patient-Derived Pancreatic Cancer Cells Induce C2C12 Myotube Atrophy by Releasing Hsp70 and Hsp90.
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DOI：
10.3390/cells11172756
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发表时间：
2022-09-03
期刊：
影响因子：
6
通讯作者：
Li, Yi-Ping
中科院分区：
文献类型：
--
作者：
Wu, Hong-Yu;Trevino, Jose G.;Fang, Bing-Liang;Riner, Andrea N.;Vudatha, Vignesh;Zhang, Guo-Hua;Li, Yi-Ping
Pancreatic cancer (PC) patients are highly prone to cachexia, a lethal wasting syndrome featuring muscle wasting with an undefined etiology. Recent data indicate that certain murine cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 through extracellular vesicles (EVs) to activate p38β MAPK-mediated catabolic pathways primarily through Toll-like receptor 4 (TLR4). However, whether human PC induces cachexia through releasing Hsp70 and Hsp90 is undetermined. Here, we investigated whether patient-derived PC cells induce muscle cell atrophy directly through this mechanism. We compared cancer cells isolated from patient-derived xenografts (PDX) from three PC patients who had cachexia (PCC) with those of three early-stage lung cancer patients without cachexia (LCC) and two renal cancer patients who were not prone to cachexia (RCC). We observed small increases of Hsp70 and Hsp90 released by LCC and RCC in comparison to non-cancer control cells (NCC). However, PCC released markedly higher levels of Hsp70 and Hsp90 (~ 6-fold on average) than LCC and RCC. In addition, PCC released similarly increased levels of Hsp70/90-containing EVs. In contrast to RCC and LCC, PCC-conditioned media induced a potent catabolic response in C2C12 myotubes including the activation of p38 MAPK and transcription factor C/EBPβ, upregulation of E3 ligases UBR2 and MAFbx, and increase of autophagy marker LC3-II, resulting in the loss of the myosin heavy chain (MHC ~50%) and myotube diameter (~60%). Importantly, the catabolic response was attenuated by Hsp70- and Hsp90-neutralizing antibodies in a dose-dependent manner. These data suggest that human PC cells release high levels of Hsp70 and Hsp90 that induce muscle atrophy through a direct action on muscle cells.
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影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
细胞外Hsp90alpha通过外泌体的分泌增加了癌细胞的运动：纤溶酶原活化的作用。
影响因子：
3.8
作者：
McCready J;Sims JD;Chan D;Jay DG
通讯作者：
Jay DG
Toll像受体（TLR）自由基周期在慢性炎症中的作用：针对TLR4途径的可能治疗方法。
影响因子：
5.1
作者：
Lucas K;Maes M
通讯作者：
Maes M
影响因子：
7.4
作者：
Pu X;Zhang R;Wang L;Chen Y;Xu Y;Pataer A;Meraz IM;Zhang X;Wu S;Wu L;Su D;Mao W;Heymach JV;Roth JA;Swisher SG;Fang B
通讯作者：
Fang B
影响因子：
5.5
作者：
McClung, J. M.;Judge, A. R.;Yan, Z.
通讯作者：
Yan, Z.