Protein kinase C iota promotes glycolysis via PI3K/AKT/mTOR signalling in high grade serous ovarian cancer.

BACKGROUND: Epithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation. METHODS AND RESULTS: Two high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC. CONCLUSION: Taken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.

Pharmacological inhibition of protein kinase D suppresses epithelial ovarian cancer via MAPK/ERK1/2/Runx2 signalling axis.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with poor prognosis and dismal patient survival. Although protein kinase D (PKD) isoforms, especially PKD2 and PKD3 are critical for many cellular and physiological functions involved in carcinogenesis including cell proliferation and angiogenesis, their role in human EOC remains unknown. Towards the goal to identify novel prognostic biomarker and therapeutic interventions against EOC, this study aimed to elucidate the molecular roles of PKD2, PKD3 and highly selective, pan-PKD inhibitor CRT0066101 in this lethal pathology. Our results indicated that inactivation of PKD2 and PKD3 by 1 µM CRT0066101 suppressed EOC cell proliferation, colony formation, cell migration and invasion. Moreover, CRT0066101 induced apoptosis and inhibited cell cycle at G2-M phase in EOC cells. Genetic knockdown of PKD2 and PKD3 confirmed the anti-carcinogenic effects of CRT0066101 against EOC. The anti-cancer phenotype of EOC cells resulted from CRT0066101-mediated PKD2 and PKD3 inactivation or genetic depletion was, in part, mediated by transcription factor Runx2 as abrogation of PKD2 and PKD3 caused downregulation of Runx2 and its downstream target genes including osteopontin, focal adhesion kinase and ERK1/2. Moreover, overexpression of a constitutively active PKD2 augmented the expression levels of phosphor-ERK1/2T202/Y204, Runx2 and its downstream targets. Mechanistically, PKD2 and PKD3 positively regulated Runx2 via MAPK/ERK1/2 pathway and promoted EOC. Taken together, our results indicated that PKD2/3/ERK1/2/Runx2 signalling axis might be a novel drug target against EOC and CRT0066101 could be developed as a promising therapeutic choice against this lethal pathology.

Runt-related transcription factors in human carcinogenesis: a friend or foe?

PURPOSE: Cancer is one of the deadliest pathologies with more than 19 million new cases and 10 million cancer-related deaths across the globe. Despite development of advanced therapeutic interventions, cancer remains as a fatal pathology due to lack of early prognostic biomarkers, therapy resistance and requires identification of novel drug targets. METHODS: Runt-related transcription factors (Runx) family controls several cellular and physiological functions including osteogenesis. Recent literatures from PubMed was mined and the review was written in comprehensive manner RESULTS: Recent literature suggests that aberrant expression of Runx contributes to tumorigenesis of many organs. Conversely, cell- and tissue-specific tumor suppressor roles of Runx are also reported. In this review, we have provided the structural/functional properties of Runx isoforms and its regulation in context of human cancer. Moreover, in an urgent need to discover novel therapeutic interventions against cancer, we comprehensively discussed the reported oncogenic and tumor suppressive roles of Runx isoforms in several tumor types and discussed the discrepancies that may have risen on Runx as a driver of malignant transformation. CONCLUSION: Runx may be a novel therapeutic target against a battery of deadly human cancers.

Human microbial dysbiosis as driver of gynecological malignancies.

Gynecological cancers that affect female reproductive tract, remain at the top of the global cancer burden list with high relapse rate and mortality. Notwithstanding development of several novel therapeutic interventions including poly-ADP-ribose polymerase inhibitors, this family of malignancies remain deadly. The human microbiome project demonstrated that dysbiosis of health resident microflora is associated with several pathologies including malignancies of the female reproductive tract and detailed characterization of species variation and host-microbe interaction could provide clues for identification of early diagnostic biomarker, preventive and therapeutic interventions. Emerging evidence suggests that several microbial signatures are significantly associated with gynecological cancers. An increased population of Proteobacteria and Firmicutes followed by significantly reduced Lactobacilli are associated with lethal epithelial ovarian cancer. Similarly, a constant association of elevated level of Atopobium vaginae, Porphyromonas somerae, Micrococci and Gardnerella vaginalis are observed in endometrial and cervical cancers. Moreover, human papilloma virus infection significantly augments colonization of pathogenic microbes including Sneathia sanguinegens, Anaerococcus tetradius, and Peptostreptococcus anaerobius and drives carcinoma of the cervix. Interestingly, microbial dysbiosis in female reproductive tract modulates expression of several microbial and immune-responsive genes such as TLR-4, TLR-5, TLR-6 and NOD-1. Therefore, stringent investigation into the microbial dysbiosis and its underlying mechanism could provide valuable cues for identification of early diagnostic biomarker, preventive and therapeutic interventions against rogue gynecological malignancies.

Recent advances in understanding the molecular role of phosphoinositide-specific phospholipase C gamma 1 as an emerging onco-driver and novel therapeutic target in human carcinogenesis.

Phosphoinositide metabolism is crucial intracellular signaling system that regulates a plethora of biological functions including mitogenesis, cell proliferation and division. Phospholipase C gamma 1 (PLCγ1) which belongs to phosphoinositide-specific phospholipase C (PLC) family, is activated by many extracellular stimuli including hormones, neurotransmitters, growth factors and modulates several cellular and physiological functions necessary for tumorigenesis such as cell survival, migration, invasion and angiogenesis by generating inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) via hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2). Cancer remains as a leading cause of global mortality and aberrant expression and regulation of PLCγ1 is linked to a plethora of deadly human cancers including carcinomas of the breast, lung, pancreas, stomach, prostate and ovary. Although PLCγ1 cross-talks with many onco-drivers and signaling circuits including PI3K, AKT, HIF1-α and RAF/MEK/ERK cascade, its precise role in carcinogenesis is not completely understood. This review comprehensively discussed the status quo of this ubiquitously expressed phospholipase as a tumor driver and highlighted its significance as a novel therapeutic target in cancer. Furthermore, we have highlighted the significance of somatic driver mutations in PLCG1 gene and molecular roles of PLCγ1 in several major human cancers, a knowledgebase that can be utilized to develop novel, isoform-specific small molecule inhibitors of PLCγ1.

Recent advancements in therapeutic targeting of the Warburg effect in refractory ovarian cancer: A promise towards disease remission.

Epithelial ovarian cancer, the most lethal gynecological malignancy, is diagnosed at advanced stage, recurs and displays chemoresistance to standard chemotherapeutic regimen of taxane/platinum drugs. Despite development of recent therapeutic approaches including poly-ADP ribose polymerase inhibitors, this fatal disease is diagnosed at advanced stage and heralds strategies for early detection and improved treatment. Recent literature suggests that high propensity of ovarian cancer cells to consume and metabolize glucose via glycolysis even in the presence of oxygen (the 'Warburg effect') can significantly contribute to disease progression and chemoresistance and hence, it has been exploited as novel drug target. This review focuses on the molecular cues of aberrant glycolysis as drivers of chemo-resistance and aggressiveness of recurrent ovarian cancer. Furthermore, we discuss the status quo of small molecule inhibition of aerobic glycolysis and significance of metabolic coupling between cancer cells and tumor microenvironment as novel therapeutic interventions against this lethal pathology.

Evaluating the current status of protein kinase C (PKC)-protein kinase D (PKD) signalling axis as a novel therapeutic target in ovarian cancer.

Ovarian cancer, especially high grade serous ovarian cancer is one of the most lethal gynaecological malignancies with high relapse rate and patient death. Notwithstanding development of several targeted treatment and immunotherapeutic approaches, researchers fail to turn ovarian cancer into a manageable disease. Protein kinase C (PKC) and protein kinase D (PKD) are families of evolutionarily conserved serine/threonine kinases that can be activated by a plethora of extracellular stimuli such as hormones, growth factors and G-protein coupled receptor agonists. Recent literature suggests that a signalling cascade initiated by these two protein kinases regulates a battery of cellular and physiological processes involved in tumorigenesis including cell proliferation, migration, invasion and angiogenesis. In an urgent need to discover novel therapeutic interventions against a deadly pathology like ovarian cancer, we have discussed the status quo of PKC/PKD signalling axis in context of this disease. Additionally, apart from discussing the structural properties and activation mechanisms of PKC/PKD, we have provided a comprehensive review of the recent reports on tumor promoting functions of PKC isoforms and discussed the potential of PKC/PKD signalling axis as a novel target in this lethal pathology. Furthermore, in this review, we have discussed the significance of several recent clinical trials and development of small molecule inhibitors that target PKC/PKD signalling axis in ovarian cancer.