Cisplatin Preferentially Binds Mitochondrial DNA and Voltage-Dependent Anion Channel Protein in the Mitochondrial Membrane of Head and Neck Squamous Cell Carcinoma: Possible Role in Apoptosis

Yang, Zhi-Zheng; Schumaker, Lisa M.; Egorin, Merrill J.; Zuhowski, Eleanor G.; Guo, Zhen; Cullen, Kevin J.

doi:10.1158/1078-0432.ccr-06-1037

Cited by 232 publications

(199 citation statements)

References 56 publications

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“…Both CDDP and OXP are mostly considered as DNA-damaging agents. However, both CDDP and OXP can induce apoptosis-associated changes in cytoplasts (Gourdier et al, 2004;Yang et al, 2006), that is, cells that have been enucleated, meaning that both of these agents have poorly characterized cytoplasmic targets, which must be at least in part agent-specific. We surmise that, in contrast to OXP, CDDP fails to affect the conformation of proteins that would cause an unfolded protein response in the ER, although the molecular details of this differential effect remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

et al. 2010

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In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2a (eIF2a). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2a phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca 2 þ -ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.

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Section: Discussionmentioning

confidence: 99%

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

et al. 2010

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“…Previous studies have shown that cisplatin-induced apoptosis can be initiated through both intrinsic and extrinsic pathways. Cisplatin induces rapid dosedependent release of cytochrome c from mitochondria to cytosol (58,59). Cytochrome c subsequently activates the caspase cascade, eventually leading to apoptotic cell death (60).…”

Section: Discussionmentioning

confidence: 99%

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

Zhu

Cao

Chao

et al. 2011

Mol Med

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Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-x L ) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-x L downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 downregulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x L and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.

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“…With regard to this, cisplatin has been shown to bind mitochondrial DNA as well as the voltage-dependent anion channel (VDAC) (Yang et al, 2006), a mitochondrial protein with vital and lethal functions (Kroemer et al, 2007). Notably, VDAC-depleted cancer cells are highly resistant to CDDP treatment (Tajeddine et al, 2008), yet it is not clear whether this constitutes an example of ontarget resistance or whether in this context VDAC simply transduces upstream proapoptotic signals (and hence would be involved in a post-target resistance mechanism).…”

Section: Mlh1mentioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Cisplatin Preferentially Binds Mitochondrial DNA and Voltage-Dependent Anion Channel Protein in the Mitochondrial Membrane of Head and Neck Squamous Cell Carcinoma: Possible Role in Apoptosis

Cited by 232 publications

References 56 publications

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

Molecular mechanisms of cisplatin resistance

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