Mitochondria and Cancer: Past, Present, and Future

Verschoor, Meghan L; Ungard, Robert; Harbottle, Andrew; Jakupciak, John P.; Parr, Ryan; Singh, Gurmit

doi:10.1155/2013/612369

Cited by 67 publications

(40 citation statements)

References 87 publications

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“…Nonselective off-target mitochondrial toxicity is a major contributor to the failure of chemotherapeutic agents in clinical practice (40,41). Recent studies of mitochondrial involvement in cancer have uncovered a plethora of differences in the structure, genome, and function of these organelles, by comparing metastatic mitochondria with those from nontransformed cells.…”

Section: Discussionmentioning

confidence: 99%

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

et al. 2015

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Mitochondria are the powerhouses of cells. Mitochondrial CRaf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its Nterminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf S338 ) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK S308 ), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF C-RafÀ/À or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity.In the presence of pDAPK S308 , this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf S338 and pDAPK S308 translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK S308 to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK S308 modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK S308 may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. Cancer Res; 75(17); 3568-82. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

et al. 2015

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“…Interestingly, growth of the provocative cells that contained the Ras mutation and mitochondrial deficiency were not activated; rather, these cells were weak and eventually dissipated. The study is among many recent reports that highlight the importance of mitochondrial activity for the tumor microenvironment (107,136).…”

Section: Effect Of Ros From Mitochondria On Cancer Transformationmentioning

confidence: 91%

Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

Scott

Rangaswamy

Wicker

et al. 2014

Antioxidants & Redox Signaling

134

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Significance: Reactive oxygen species (ROS) are generated by exogenous and environmental genotoxins, but also arise from mitochondria as byproducts of respiration in the body. ROS generate DNA damage of which pathological consequence, including cancer is well established. Research efforts are intense to understand the mechanism of DNA base excision repair, the primary mechanism to protect cells from genotoxicity caused by ROS. Recent Advances: In addition to the notion that oxidative DNA damage causes transformation of cells, recent studies have revealed how the mitochondrial deficiencies and ROS generation alter cell growth during the cancer transformation. Critical Issues: The emphasis of this review is to highlight the importance of the cellular response to oxidative DNA damage during carcinogenesis. Oxidative DNA damage, including 7,8-dihydro-8-oxoguanine, play an important role during the cellular transformation. It is also becoming apparent that the unusual activity and subcellular distribution of apurinic/apyrimidinic endonuclease 1, an essential DNA repair factor/redox sensor, affect cancer malignancy by increasing cellular resistance to oxidative stress and by positively influencing cell proliferation. Future Directions: Technological advancement in cancer cell biology and genetics has enabled us to monitor the detailed DNA repair activities in the microenvironment. Precise understanding of the intracellular activities of DNA repair proteins for oxidative DNA damage should provide help in understanding how mitochondria, ROS, DNA damage, and repair influence cancer transformation. Antioxid. Redox Signal. 20,[708][709][710][711][712][713][714][715][716][717][718][719][720][721][722][723][724][725][726]

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“…It is a highly sensitive test that yields accurate and reliable results. This test can detect large-scale mtDNA deletions (3.4 kb) in normal/benign appearing tissues obtained by biopsy via a ‘cancerization’ field effect [19, 59, 60]. In this assay, a section of the needle core sample from the negative biopsy is employed to assess the occurrence of 3.4 kb mtDNA deletions using real time PCR.…”

Section: Prostate Cancer Biomarkers: Non-fda Approved Clinical Labmentioning

confidence: 99%

PSA and beyond: alternative prostate cancer biomarkers

2016

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Background The use of biomarkers for prostate cancer screening, diagnosis and prognosis has the potential to improve the clinical management of the patients. Owing to inherent limitations of the biomarker prostate-specific antigen (PSA), intensive efforts are currently directed towards a search for alternative prostate cancer biomarkers, particularly those that can predict disease aggressiveness and drive better treatment decisions. Methods A literature search of Medline articles focused on recent and emerging advances in prostate cancer biomarkers was performed. The most promising biomarkers that have the potential to meet the unmet clinical needs in prostate cancer patient management and/or that are clinically implemented were selected. Conclusions With the advent of advanced genomic and proteomic technologies, we have in recent years seen an enormous spurt in prostate cancer biomarker research with several promising alternative biomarkers being discovered that show an improved sensitivity and specificity over PSA. The new generation of biomarkers can be tested via serum, urine, or tissue-based assays that have either received regulatory approval by the US Food and Drug Administration or are available as Clinical Laboratory Improvement Amendments-based laboratory developed tests. Additional emerging novel biomarkers for prostate cancer, including circulating tumor cells, microRNAs and exosomes, are still in their infancy. Together, these biomarkers provide actionable guidance for prostate cancer risk assessment, and are expected to lead to an era of personalized medicine.

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Mitochondria and Cancer: Past, Present, and Future

Cited by 67 publications

References 87 publications

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

PSA and beyond: alternative prostate cancer biomarkers

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