Medical Sciences Commons^™

Elevated Paf1-Rad52 Axis Confers Chemoresistance To Human Cancers, Sanchita Rauth, Koelina Ganguly, Pranita Atri, Seema Parte, Rama Krishna Nimmakayala, Venkatesh Varadharaj, Palanisamy Nallasamy, Raghupathy Vengoji, Ayoola O. Ogunleye, Imayavaramban Lakshmanan, Ramakanth Chirravuri, Mika Bessho, Jesse L. Cox, Jason M. Foster, Geoffrey A. Talmon, Tadayoshi Bessho, Apar Kishor Ganti, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression …

The Gsk3 Kinase And Lztr1 Protein Regulate The Stability Of Ras Family Proteins And The Proliferation Of Pancreatic Cancer Cells, Chitra Palanivel, Neha Chaudhary, Parthasarathy Seshacharyulu, Jesse L. Cox, Ying Yan, Surinder K. Batra, Michel M. Ouellette

Journal Articles: Biochemistry & Molecular Biology

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated …

Amyloid Precursor-Like Protein 2 Expression Increases During Pancreatic Cancer Development And Shortens The Survival Of A Spontaneous Mouse Model Of Pancreatic Cancer., Brittany J. Poelaert, Shelby M. Knoche, Alaina C. Larson, Poomy Pandey, Parthasarathy Seshacharyulu, Nuzhat Khan, H. Carlo Maurer, Kenneth P. Olive, Yuri Sheinin, Rizwan Ahmad, Amar B. Singh, Surinder K. Batra, Satyanarayana Rachagani, Joyce C. Solheim

Journal Articles: Biochemistry & Molecular Biology

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered …

Repurposing Niclosamide For Targeting Pancreatic Cancer By Inhibiting Hh/Gli Non-Canonical Axis Of Gsk3Β, Jyoti B. Kaushal, Rakesh Bhatia, Ranjana K. Kanchan, Pratima Raut, Surya Mallapragada, Quan P. Ly, Surinder K. Batra, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive …

Vitamin E Δ-Tocotrienol Sensitizes Human Pancreatic Cancer Cells To Trail-Induced Apoptosis Through Proteasome-Mediated Down-Regulation Of C-Flip, Rony A. Francois, Anying Zhang, Kazim Husain, Chen Wang, Sean Hutchinson, Michael Kongnyuy, Surinder K. Batra, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa

Journal Articles: Biochemistry & Molecular Biology

Background: Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.

Methods: We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.

Results: When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, …

Pancreatic Cancer Associated With Obesity And Diabetes: An Alternative Approach For Its Targeting, Ramesh Pothuraju, Satyanarayana Rachagani, Wade M. Junker, Sanjib Chaudhary, Saraswathi Viswanathan, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure.

MAIN BODY: Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different …

Targeting Egf-Receptor(S) - Stat1 Axis Attenuates Tumor Growth And Metastasis Through Downregulation Of Muc4 Mucin In Human Pancreatic Cancer., Parthasarathy Seshacharyulu, Moorthy P. Ponnusamy, Satyanarayana Rachagani, Imayavaramban Lakshmanan, Dhanya Haridas, Y Yan, Apar Kishor Ganti, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, …

A Concise Review On The Current Understanding Of Pancreatic Cancer Stem Cells., Arokia P. Vaz, Moorthy P. Ponnusamy, Parthasarathy Seshacharyulu, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

No abstract provided.

Pd2/Paf1 Depletion In Pancreatic Acinar Cells Promotes Acinar-To-Ductal Metaplasia., Parama Dey, Satyanarayana Rachagani, Arokia P. Vaz, Moorthy P. Ponnusamy, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of KrasG12D/Pdx1Cre (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas …