Mcl-1 is downregulated in cisplatin-induced apoptosis, and proteasome inhibitors restore Mcl-1 and promote survival in renal tubular epithelial cells

Yang, Cheng‐Ta; Kaushal, Varsha; Shah, Sudhir V.; Kaushal, Gur P.

doi:10.1152/ajprenal.00505.2006

Cited by 36 publications

(25 citation statements)

References 59 publications

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“…Given the critical role that Bcl-2 family proteins and p53 protein play in apoptosis regulation (12,66), expression of these apoptosis-related molecules was monitored. In line with a previous report (64) showing that cisplatin induces reduction of Mcl-1 in renal tubular epithelial cells, protein levels of Mcl-1 exhibited mild decreases in HepG2-con cells after exposure to cisplatin; interestingly, levels of Mcl-1 displayed even more dramatic decreases in HepG2-HBx cells than in control cells after cisplatin treatment ( Fig. 2A).…”

Section: Resultssupporting

confidence: 92%

“…In view of the key role of the Bcl-2 protein family in the regulation of cell survival and death, we examined the expression of several Bcl-2 family members. Interestingly, among the apoptosis-related proteins detected, only protein levels of Mcl-1 were reduced dramatically in HBx-expressing hepatocytes following treatment with cisplatin, which was consistent with the finding of a previous study that Mcl-1 was downregulated during cisplatin-induced apoptosis in renal tubular epithelial cells (64). Furthermore, similar results were also observed in an HBx-inducible expression system, HBVreplicating HepG2.2.15 cells, and SMMC-7721 cells transfected with the wild-type but not HBx-mutated HBV genome.…”

Section: Discussionsupporting

confidence: 91%

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Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Chen

Liang

et al. 2011

J Virol

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Chen

Liang

et al. 2011

J Virol

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“…Sorafenib, a Food and Drug Administration-approved agent in the treatment of renal cell carcinoma, has been shown to decrease Mcl-1 in an AML model (32). Cisplatin, a first-line agent in the treatment of SCLC, decreases Mcl-1 levels in human renal tubular epithelial cells (33). The primary xenografts may serve as representative models that test combinatorial therapies with agents that down-regulate multiple members of the Bcl-2 family.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer

et al. 2008

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Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321-8]

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“…Gemcitabine is the first-line chemotherapeutic agent for advanced adenocarcinoma of pancreatic cancer; however, chemoresistance to gemcitabine remains a major cause of failure for the clinical treatment of this disease. Studies have indicated that resistance to gemcitabine is dependent on mitochondria-mediated apoptosis, but various mediators of gemcitabine-mediated apoptosis have been described (40)(41)(42)(43). The precise mechanism is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells

Pan

Song

et al. 2012

Oncol Rep

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Abstract. CD147, which belongs to the immunoglobulin superfamily, is a multifunctional glycoprotein that has been shown to increase tumor invasion, metastasis and multidrug resistance. To define the role of CD147 in invasion and metastasis more precisely, we utilized gene silencing to inhibit the expression of CD147 in pancreatic cancer cells. We observed that CD147 expression was significantly impeded at both the mRNA and protein levels and resulted in a decrease of MMP-2 and MMP-9 activities. There was also a decrease of MCT1 expression in the invasion and metastasis potential of pancreatic cancer cells, as well as increased chemosensitivity to gemcitabine in Panc-1 cells. Overall, these results suggest that CD147 plays an important role in the invasion, metastasis and chemosensitivity of the human pancreatic cancer cell line Panc-1, indicating that CD147 may be a promising therapeutic target for pancreatic cancer. IntroductionPancreatic cancer is a malignancy with an extremely poor prognosis and is refractory to conventional chemotherapy and radiotherapy. Despite efforts in the past years, conventional treatment approaches, such as surgery, radiation, chemotherapy, or combinations of these, the mortality rate of pancreatic cancer still remains high (1-4). Therefore, it can be effectively diagnosed, prevented, and treated only by developing a detailed understanding of the molecular biology of underlying pancreatic cancer formation and progression.CD147 (EMMPRIN) is a highly glycosylated cell surface transmembrane protein that belongs to the immunoglobulin superfamily (5), and it is thought to be involved in inflammation, neural-glial interaction, and virus infection (6-9). CD147 is found to be highly expressed in a variety of malignant human cancers, including malignancies of the pancreas (6,10,11), and it induces tumor cell invasion by stimulating the production of matrix metalloproteinases (MMPs), resulting in tumor invasion and metastasis (12). In addition, CD147 plays a pivotal role as a chaperone for the proper plasma membrane expression and the activity of monocarboxylate transporters (MCTs), particularly MCT1 and MCT4 (13-15). MCTs are among the most important cellular pH regulators likely involved in cancer pH homeostasis (16-18). The MCT family has fourteen members (19), six of which have been functionally characterized, but only MCT1-MCT4 have been shown to catalyze the proton-coupled transport of lactate (20)(21)(22)(23)(24). Many studies have demonstrated that CD147 acts as an essential chaperone to take MCT1 and MCT4 to the plasma membrane where the MCTs and CD147 are tightly associated (13,25).CD147 is also involved in multidrug resistance of cancer cells via hyaluronan-mediated activation of ErbB2 signaling and cell survival pathway activities, but the mechanism of CD147 in multidrug resistance of pancreatic cancer remains elusive (26-28). We demonstrate here that CD147 silencing inhibits pancreatic cancer cell invasion and metastasis and increases chemosensitivity to gemcitabine. Our results su...

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Mcl-1 is downregulated in cisplatin-induced apoptosis, and proteasome inhibitors restore Mcl-1 and promote survival in renal tubular epithelial cells

Cited by 36 publications

References 59 publications

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer

CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells

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