Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis

Wang, Peng; Song, Jin H.; Song, Doyoun K.; Zhang, Jing; Hao, Chunhai

doi:10.1016/j.cellsig.2005.12.004

Cited by 58 publications

(48 citation statements)

References 17 publications

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“…Moreover, in contrast to the activation of Caspase-8 even in the lower drug dose of RT4-treated cells, which unambiguously confirms their increased sensitivity to the drug, T24 were not only unable for a respective response, but they were also missing the 18 kDa small fragment, likely implying an inability to form the mature and fully active tetramer of Caspase-8, and an attenuation of the Caspase-8-mediated downstream signaling pathways. In agreement with our results, proteolytic processing and activation of initiator and effector Caspases have been also reported before in Jurkat T leukemia cells, MCF-7 breast cancer cells and human osteosarcoma (HOS) cells after cisplatin administration (6,(49)(50)(51). Notably, cisplatin apoptotic activity in Jurkat T leukemia cells was shown to be independent of membrane death receptors, while mitochondria contribution was definitely required (49).…”

Section: Discussionsupporting

confidence: 79%

“…The first one involves Caspase-8, which is activated through membrane death receptor-mediated extrinsic pathways, whereas the second one implicates mitochondria-emanated intrinsic pathways, being mainly characterized by activation of Caspase-9 via Cytochrome c release into the cytosol and apoptosome formation (an Apaf-1-and ATP-dependent process). Subsequently, activated Caspase-3, as the major effector component of both pathways, initiates a program of proteolytic cleavages of critical cellular proteins, including PARP and Lamin A/C, eventually resulting to apoptosis (6,26,33,47,49).…”

Section: Discussionmentioning

confidence: 99%

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Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Konstantakou

Voutsinas²,

Karkoulis³

et al. 2009

Int J Oncol

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Abstract.Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNAPt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Fas, FasL, TRAIL, Puma, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells. IntroductionWith its incidence continuing to increase, bladder cancer is classified among the five most common malignancies in industrialized countries (1). Forming a worldwide estimate over one million patients, bladder cancer is clearly considered a significant public health issue around the world (2). The three main types of cancer affecting bladder are transitional cell carcinoma (TCC), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), with TCC representing >90% of all bladder cancers. Four clinically distinct entities of TCC have been recognized: superficial, papillary tumors (Ta and T1), carcinoma in situ (Tis), muscle-invasive tumors (T2-T4) and advanced disease, involving extra-pelvic nodal or distant metastasis (3,4). Metastatic TCC demonstrates a moderate sensitivity to chemotherapy while a significant variation in patient survival rates and activity levels of individual regimens has been observed (5).Cisplatin-based combination chemotherapy protocols, such as MVAC (methotrexate-vinblastine-adriamycin-cisplatin), constituted for a number of years standard treatment of patients with advanced (or metastatic) urothelial bladder cancer. However, due to the MVAC-induced systemic toxici...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Konstantakou

Voutsinas²,

Karkoulis³

et al. 2009

Int J Oncol

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“…For instance, cisplatin induces apoptosis in Jurkat cells through ROS-dependent Fas aggregation and activation of the FADD-caspase 8 cascade. 61 In addition, UDCA as a membrane stabilizer has been described, suggesting the possible relationship of death mode regulatory mechanisms with membrane-associated events. 62,63 On the other hand, caspase 8 can also be activated by a FADDindependent mechanism including the mitochondrial pathway.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim

Choi

Kang

2010

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancer-related mortality, and it generally represents highly resistant features to chemotherapy.1-3 Surgical resection and liver transplantation might be the most effective way to cure the cancer, but these approaches have limited applicability and advanced tumors frequently recur even after complete surgical resection. 4,5 Hence, chemotherapy remains an important option to treat HCC and developments of new chemotherapeutic strategies are necessary.Oxaliplatin, a third generation platinum-based chemotherapeutic agent, displays a broader spectrum of antitumor activity than cisplatin and carboplatin and no cross-resistance against some cisplatin-and carboplatin-resistant tumors. [6][7][8][9] Currently, it is widely used as a basis of combination regimens for various cancers including gastric, colorectal and advanced nasopharyngeal carcinoma. [10][11][12] In addition, several oxaliplatin-combined regimens have been used for patients with advanced HCC and these have shown a moderate but promising anti-tumor effect. 13,14

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“…TRAIL has been shown to induce apoptosis selectively in a variety of cancer cell lines but not in normal cells (1,2). Induction of apoptosis by TRAIL is mediated by its interaction with two death domain-containing receptors, TRAIL-R1/ DR 4 and TRAIL-R2/DR 5 .…”

Section: Introductionmentioning

confidence: 99%

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

Guo

Liu²,

Liu³

et al. 2011

Oncol Rep

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Abstract. Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells or transformed cells, yet, it is relatively non-toxic to most normal cells. Consequently, TRAIL was thought to be a promising agent for cancer therapy. However, recent research reports revealed that many tumors are unresponsive to TRAIL treatment. Apoptotic agents were identified that when used in combination with TRAIL can sensitize tumor cells to TRAILmediated apoptosis. It was demonstrated that MEKK3-siRNA sensitized MCF-7 cells to TRAIL cytoxicity. In addition, we investigated the discrepancy of the expression of MEKK3 in breast cancers. It was concluded that elevated MEKK3 expression is found at high frequencies in breast cancer compared to normal breast tissue. Further experiments on the signal machinery showed that MEKK3-siRNA increased the sensitivity of MCF-7 cells to TRAIL by suppressing the transcription activity of NF-κB, and enhancing the caspaseprocessing to generate executive apoptotic signals. These findings indicate that down-regulation of MEKK3 by siRNA approaches will lead to successful treatment of human breast cancer with TRAIL.

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Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis

Cited by 58 publications

References 17 publications

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB

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