Bcl‐xL protein: Predictor of complete tumor response in patients with oral cancer treated with curative radiotherapy

Mallick, Sanchita; Agarwal, Jitendra; Kannan, Sadhana; Pawar, Sagar; Kane, Shubhada; Teni, Tanuja

doi:10.1002/hed.23153

Cited by 9 publications

(11 citation statements)

References 40 publications

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“…Other molecular biomarkers including epidermal growth factor receptor (EGFR), B-cell lymphoma extra large (Bcl-xL), p53, and Ki67, have been shown to have prognostic significance i [3]. High EGFR expression has been correlated with poorer survival, while low levels of the anti-apoptotic protein, Bcl-xL, have been shown to be associated with improved response to radiation [4]. A recent study has suggested that elevated Ki67 levels may be associated with improved response to radiotherapy [5].…”

Section: Introductionmentioning

confidence: 99%

Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma

Barber

Biron

Klimowicz

et al. 2013

Journal of Otolaryngology - Head & Neck Surgery

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BackgroundThe incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing due to fundamental changes in oncogenesis related to effects of the human papilomavirus (HPV). Virally-mediated tumours behave and respond to treatment differently than their classic, carcinogenically-mediated counterparts despite similar stage and grade of disease. This difference in behaviour has lead to investigation of etiologies of OPSCC at the molecular level.Molecular biomarkers offer potential insight into the behaviour of OPSCC. Identifying a subset of patients that are more likely to have recurrence and distant metastasis is valuable for prognostication and treatment planning. There is limited information regarding the profiles of these biomarkers in locoregional and distant metastases in OPSCC.ObjectiveThis study was designed to identify biomarker profiles predictive of locoregional and distant metastases and recurrence in OPSCC.MethodsCross-sectional study of a prospectively-collected oropharyngeal tumour database was undertaken. All patients with OPSCC presenting to the University of Alberta Hospital from 2002-2009 were included in the study. Data collection from the Alberta Cancer Registry, including demographics, nodal status, distant metastases, treatment, recurrence, and survival, was undertaken. Tissue micro-arrays (TMAs) were constructed for each tumour specimen using triplicate cores (0.6mm) of formalin-fixed, paraffin-embedded (FFPE) pre-treatment tumour tissue. TMAs were processed using immunohistochemistry for p16, EGFR, Ki67, p53, and Bcl-XL. Positivity for each biomarker was determined using quantified AQUAnalysis ® scores on histoplots. Multivariate statistics were utilized to assess the relationship between each biomarker and locoregional and distant metastases, as well as recurrence-free survival (RFS).ResultsHigh expression of p16 (p=0.000) and Bcl-XL (p=0.039) independently demonstrated a significant association with nodal disease at presentation. Kaplan-Meier analysis demonstrated improved RFS in patients with high p16 and decreased RFS in patients with high p53 expression. Cox regression analysis supported p16 as an independent prognosticator for improved RFS. p53 demonstrated an association with recurrence, but when compared to p16 status, nodal status, and staging, was not an independent predictor of recurrence.ConclusionsBiomarker profiling using p16, Bcl-xL, and p53 may be useful in prognostication and treatment planning in patients with OPSCC.

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Section: Introductionmentioning

confidence: 99%

Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma

Barber

Biron

Klimowicz

et al. 2013

Journal of Otolaryngology - Head & Neck Surgery

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“…Aberrant expression of antiapoptotic BCL-2 family proteins, particularly MCL-1 has been reported in diverse human cancers including oral cancers [ 16 , 52 ]. We have earlier demonstrated that the prosurvival MCL-1 protein contributes to therapy resistance and poor prognosis in oral cancers and thus may prove to be a potential therapeutic target in OSCC [ 15 , 17 – 19 ]. Hence in the present study, we evaluated the efficacy of a BH3-mimetic pan-BCL-2 inhibitor Obatoclax against human oral cancer cell lines and also elucidated the mechanism of its action.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptotic dysregulation is believed to be one of the key underlying reason for the progression of OSCC [ 11 ]. BCL-2 and BCL-XL overexpression correlates with therapy resistance and poor prognosis in OSCC [ 12 – 15 ]. We have previously reported overexpression of anti-apoptotic members of the BCL-2 family, particularly MCL-1 (Myeloid Cell Leukemia-1) over their pro-apoptotic counterparts in human oral cancers [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

BH3 mimetic Obatoclax (GX15-070) mediates mitochondrial stress predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells

Sulkshane

Teni

2016

Oncotarget

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We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200–400 nM concentration which correlated with their MCL-1 expression. Mechanistic insights revealed that Obatoclax induced a caspase-independent cell death primarily by induction of a defective autophagy. Suppression of autophagy by ATG5 downregulation significantly blocked Obatoclax-induced cell death. Further, Obatoclax induced interaction of p62 with key components of the necrosome RIP1K and RIP3K. Necrostatin-1 mediated inhibition of RIP1K significantly protected the cells from Obatoclax induced cell death. Moreover, Obatoclax caused extensive mitochondrial stress leading to their dysfunction. Interestingly, MCL-1 downregulation alone caused mitochondrial stress, highlighting its importance for mitochondrial homeostasis. We also demonstrated in vivo efficacy of Obatoclax against oral cancer xenografts and its synergism with ionizing radiation in vitro. Our studies thus suggest that Obatoclax induces autophagy-dependent necroptosis in oral cancer cells and holds a great promise in the improved management of oral cancer patients.

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“…Interestingly, Bcl-xL is very rarely mutated in human tumors, suggesting that putative key mutations within Bcl-xL would be unsuitable for cell proliferation and survival (see mutations and polymorphisms in S3 Fig ). Bcl-xL overexpression rather than mutation is associated with tumor development and poor treatment response in various cancers [ 35 – 41 ]. Indeed, tumor cells are believed to depend on, or are addicted to, anti-apoptotic Bcl-2 family members, including Bcl-xL [ 42 ], providing a selective advantage to cancer cells by allowing them to survive various stressful environments, cell stress phenotypes and/or cell death signals that directly ensue from oncogenic signaling, tumor suppressor deficiency or anticancer treatments [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamic Bcl-xL (S49) and (S62) Phosphorylation/Dephosphorylation during Mitosis Prevents Chromosome Instability and Aneuploidy in Normal Human Diploid Fibroblasts

2016

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Bcl-xL proteins undergo dynamic phosphorylation/dephosphorylation on Ser49 and Ser62 residues during mitosis. The expression of Bcl-xL(S49A), (S62A) and dual (S49/62A) phosphorylation mutants in tumor cells lead to severe mitotic defects associated with multipolar spindle, chromosome lagging and bridging, and micro-, bi- and multi-nucleated cells. Because the above observations were made in tumor cells which already display genomic instability, we now address the question: will similar effects occur in normal human diploid cells? We studied normal human diploid BJ foreskin fibroblast cells expressing Bcl-xL (wild type), (S49A), (S49D), (S62A), (S62D) and the dual-site (S49/62A) and (S49/62D) mutants. Cells expressing S49 and/or S62 phosphorylation mutants showed reduced kinetics of cell population doubling. These effects on cell population doubling kinetics correlated with early outbreak of senescence with no impact on the cell death rate. Senescent cells displayed typical senescence-associated phenotypes including high-level of senescence-associated β-galactosidase activity, interleukin-6 (IL-6) secretion, tumor suppressor p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 activation as well as γH2A.X-associated nuclear chromatin foci. Fluorescence in situ hybridization analysis and Giemsa-banded karyotypes revealed that the expression of Bcl-xL phosphorylation mutants in normal diploid BJ cells provoked chromosome instability and aneuploidy. These findings suggest that dynamic Bcl-xL(S49) and (S62) phosphorylation/dephosphorylation cycles are important in the maintenance of chromosome integrity during mitosis in normal cells. They could impact future strategies aiming to develop and identify compounds that could target not only the anti-apoptotic domain of Bcl-xL protein, but also its mitotic domain for cancer therapy.

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Bcl‐xL protein: Predictor of complete tumor response in patients with oral cancer treated with curative radiotherapy

Abstract: Our study suggests that Bcl-xL expression along with clinical parameters may be useful for identifying patients with oral cancer likely to draw maximum benefit from curative radiotherapy.

Cited by 9 publications

References 40 publications

Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma

Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma

BH3 mimetic Obatoclax (GX15-070) mediates mitochondrial stress predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells

Dynamic Bcl-xL (S49) and (S62) Phosphorylation/Dephosphorylation during Mitosis Prevents Chromosome Instability and Aneuploidy in Normal Human Diploid Fibroblasts

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