Cyclosporine blocks muscle differentiation by inducing oxidative stress and by inhibiting the peptidylprolyl‐cistrans‐isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporine‐induced cytotoxicity

Hong, Feng; Lee, Jinhwa; Song, Jaewoo; Lee, Su Jae; Ahn, Hyung‐Joon; Cho, Jeong Je; Ha, Joohun; Kim, Sung Soo

doi:10.1096/fj.02-0060fje

Cited by 109 publications

(78 citation statements)

References 48 publications

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“…Although little is known about the function of CypA in cancer cells, it was recently reported that CypA is overexpressed in many cancer cells (6)(7)(8)(9)(10)(11). In addition, our studies, as well as others, previously showed that overexpressed CypA protects cancer cells against cellular stresses, including hypoxia and cisplatin treatment, at least in part as a result of its antioxidant function (12)(13)(14)(15). These reports show that CypA might be important for tumorigenesis in solid tumors.…”

Section: Introductionsupporting

confidence: 76%

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Han

Yoon²,

Ding³

et al. 2010

Oncol Rep

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Abstract. Glioma is the most common type of brain tumors in adults, and treatment of high-grade gliomas is still palliative. Studies to date have revealed only modest effect in attenuating growth of these tumors with single agent therapy, but combination treatment appears to be more effective. Cyclophilin A (CypA), a target of immunosuppressive drugs cyclosporin A (CsA) and sanglifehrin A (SFA), is an intracellular protein that has peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity. Previously, we showed that overexpressed CypA induced chemoresistance in cancer cells. Here we provide evidence that combination of cisplatin with either CsA or SFA synergistically enhances apoptotic cell death in C6 glioma cells, compared with single agent treatment. Enhanced apoptotic cell death is a result of an increase in ROS generation and a decrease in intracellular glutathione levels. Consistently, CypA knockdown by siRNA also enhances cisplatin-induced apoptosis. Immunohistochemical analysis showed increased expression of CypA in human glioblastoma multiforme, but not in normal human astrocytes. CypA was also shown to be up-regulated in C6 glioma cells during hypoxia. In conclusion, CsA or SFA in combination with cisplatin synergistically enhances cisplatin-induced apoptosis in C6 glioma cells via inhibition of PPIase activity of CypA, indicating that development of new drugs that selectively inhibit the CypA PPIase activity without immune suppression may facilitate alleviation of chemoresistance in treatment of high-grade glioma. IntroductionGlioma is the most common type of brain tumors in adults, and accounts for 25% of all brain tumors (1,2). Despite significant advances in cancer therapy, treatment of high-grade gliomas is still palliative. To date, the median survival for patients with high-grade gliomas, including glioblastoma multiforme (GBM; World Health Organization grade IV), is less than 1 year (3,4). Therefore, improved systemic treatment strategies are urgently required.Cyclophilin A (CypA), the prototypical member of the cyclophilin family, is a highly conserved protein in mammalian cells (5). CypA possesses enzymatic peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is essential for protein folding in vivo. Although little is known about the function of CypA in cancer cells, it was recently reported that CypA is overexpressed in many cancer cells (6-11). In addition, our studies, as well as others, previously showed that overexpressed CypA protects cancer cells against cellular stresses, including hypoxia and cisplatin treatment, at least in part as a result of its antioxidant function (12)(13)(14)(15). These reports show that CypA might be important for tumorigenesis in solid tumors. CypA is also an immunophilin and a cytosolic receptor for the immunosuppressive drugs cyclosporin A (CsA) (5) and sanglifehrin A (SFA) (16). CsA binds to CypA, and this complex inhibits calcineurin, a calcium-dependent phosphatase, that regulates the expression of various cytokine genes ONCOLOGY REPORTS 2...

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Section: Introductionsupporting

confidence: 76%

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Han

Yoon²,

Ding³

et al. 2010

Oncol Rep

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“…In addition, genes involved in mitochondrial function and redox potential also are markedly altered in MyoD Ϫ/Ϫ myoblasts. MyoD deficiency may protect myoblasts from generating reactive oxygen species and stimulating mitochondria, which can trigger release of cytochrome C, a mitochondrial initiator of major apoptosis cascades (34,35). In any case, the evidence for substantially increased survival of engrafted MyoD Ϫ/Ϫ myoblasts after transplantation into damaged muscle provides reason to believe that they may effectively improve muscle function compared with wild-type myoblasts.…”

Section: Discussionmentioning

confidence: 99%

Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle

Asakura

Hirai

Kablar

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

107

114

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MyoD is a myogenic master transcription factor that plays an essential role in muscle satellite cell (muscle stem cell) differentiation. To further investigate the function of MyoD in satellite cells, we examined the transplantation of satellite cell-derived myoblasts lacking the MyoD gene into regenerating skeletal muscle. After injection into injured muscle, MyoD ؊/؊ myoblasts engrafted with significantly higher efficiency compared with wild-type myoblasts. In addition, MyoD ؊/؊ myoblast-derived satellite cells were detected underneath the basal lamina of muscle fibers, indicating the self-renewal property of MyoD ؊/؊ myoblasts. To gain insights into MyoD gene deficiency in muscle stem cells, we investigated the pathways regulated by MyoD by GeneChip microarray analysis of gene expression in wild-type and MyoD ؊/؊ myoblasts. MyoD deficiency led to down-regulation of many muscle-specific genes and up-regulation of some stem cell markers. Importantly, in MyoD ؊/؊ myoblasts, many antiapoptotic genes were up-regulated, whereas genes known to execute apoptosis were downregulated. Consistent with these gene expression profiles, MyoD ؊/؊ myoblasts were revealed to possess remarkable resistance to apoptosis and increased survival compared with wild-type myoblasts. Forced expression of MyoD or the proapoptotic protein Puma increased cell death in MyoD ؊/؊ myoblasts. Therefore, MyoD ؊/؊ myoblasts may preserve stem cell characteristics, including their resistance to apoptosis, expression of stem cell markers, and efficient engraftment and contribution to satellite cells after transplantation. Furthermore, our data offer evidence for improved therapeutic stem cell transplantation for muscular dystrophy, in which suppression of MyoD in myogenic progenitors would be beneficial to therapy by providing a selective advantage for the expansion of stem cells.apoptosis ͉ cell therapy ͉ microarrays ͉ muscular dystrophy ͉ satellite cell

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“…We previously found that H 2 O 2 originating from Nox2 stimulates muscle differentiation via the NF-κB activation/iNOS expression pathway, and that PI3K is upstream of the Nox2/NF-κB/iNOS pathway [15,27,28]. As a npg result of increased iNOS expression, nitric oxide (NO) production was enhanced during muscle differentiation.…”

Section: C-ras Regulates Downstream Signaling Molecules Of Pi3kmentioning

confidence: 99%

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-κB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-κB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/ Mek/Erk pathway.

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Cyclosporine blocks muscle differentiation by inducing oxidative stress and by inhibiting the peptidylprolyl‐cistrans‐isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporine‐induced cytotoxicity

Cited by 109 publications

References 48 publications

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

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