Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival.
Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival.
复制标题
DOI：
10.1186/1476-4598-11-20
复制
发表时间：
2012-04-05
期刊：
影响因子：
37.3
通讯作者：
Rempel SA
中科院分区：
文献类型：
--
作者：
Schultz CR;Golembieski WA;King DA;Brown SL;Brodie C;Rempel SA
目前对胶质瘤患者的治疗方案是手术，然后是放射治疗加替莫唑胺(TMZ)，然后是6个月的辅助TMZ。尽管有这种积极的治疗方案，所有接受手术治疗的GBM患者的总体存活率仍然很低，需要额外或不同的治疗方法。根据癌症的类型，SPARC既被认为是治疗的靶点，也被认为是一种治疗剂。在胶质瘤中，SPARC通过上调p38MAPK/MAPKAPK2/HSP27信号通路促进肿瘤侵袭，并通过上调pakt促进肿瘤细胞存活。由于HSP27和AKT相互作用调节彼此的活性，我们确定作为一种治疗方法，抑制HSP27是否比靶向SPARC更能抑制SPARC诱导的胶质瘤细胞的侵袭和存活。我们的研究发现以下几点。1)SPARC平衡增加肿瘤细胞促生存和促死亡蛋白信号的表达，使肿瘤细胞存活保持不变。2)抑制SPARC可提高肿瘤细胞存活率，表明其不是良好的治疗靶点。3)在所有胶质瘤中，抑制HSP27可降低肿瘤细胞的存活率，但在表达SPARC的肿瘤细胞中更为有效，因为HSP27对SPARC诱导的促凋亡信号的抑制作用被解除。4)抑制总AKT1/2反常地提高肿瘤细胞存活率，表明AKT1或2是不良的治疗靶点。5)然而，抑制PAKT会抑制肿瘤细胞的存活。6)同时抑制HSP27和PAKT可协同降低肿瘤细胞存活率。7)SPARC、HSP27和AKT之间似乎存在一个复杂的反馈系统。8)这种相互作用可能受PTEN状态的影响。关于化学增敏，我们发现了以下几点。1)SPARC增强TMZ暴露细胞的促凋亡信号转导。2)尽管信号转导增强，SPARC保护细胞免受TMZ的侵袭。3)这种保护作用可以通过抑制PAKT来减弱。4)HSP27和PAKT联合应用较单用TMZ更有效。我们的结论是，单独抑制HSP27或与PAKT抑制剂IV联合应用可能是抑制SPARC诱导的胶质瘤细胞侵袭和存活的有效方法。
The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ), followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Our studies found the following. 1) SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2) Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3) Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4) Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5) However, inhibiting pAKT suppresses tumor cell survival. 6) Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7) There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8) This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1) SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2) Despite this enhanced signaling, SPARC protects cells against TMZ. 3) This protection can be reduced by inhibiting pAKT. 4) Combined inhibition of HSP27 and pAKT is more effective than TMZ treatment alone. We conclude that inhibition of HSP27 alone, or in combination with pAKT inhibitor IV, may be an effective therapeutic approach to inhibit SPARC-induced glioma cell invasion and survival in SPARC-positive/PTEN-wildtype and SPARC-positive/PTEN-null tumors, respectively.
登录
查看更多内容
影响因子：
3.7
作者：
Estrugo D;Fischer A;Hess F;Scherthan H;Belka C;Cordes N
通讯作者：
Cordes N
影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
DOI：
10.1016/j.bbrc.2008.03.042
发表时间：
2008-05-23
影响因子：
3.1
作者：
Hara, Shingo;Nakashiro, Koh-ichi;Hamakawa, Hiroyuki
通讯作者：
Hamakawa, Hiroyuki
影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
4.8
作者：
Barker, TH;Baneyx, G;Sage, EH
通讯作者：
Sage, EH