Biology subjects

Nengroo, M. A.

Publications and source records attributed to Nengroo, M. A..

5 recordsLinked to original sources

bioRxiv2025

Succinate dehydrogenase activity supports de novo purine synthesis

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

biochemistry↗

bioRxiv2023

PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of SLC7A11 (System Xc-)

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

cancer biology↗

bioRxiv2021

H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

Triple Negative Breast Cancer (TNBC) is known to have poor prognosis and adverse clinical outcome among all breast cancer subtypes due to the absence of available targeted therapy for it. Emerging literature indicates that epigenetic reprogramming is now appreciated as a driving force for TNBC pathophysiology. High expression of epigenetic modulator EZH2 (Enhancer of zeste homolog 2) has been shown to correlate with TNBC poor prognosis but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC growth and progression remains elusive. In the process of dissecting the impact of H3K27me3 versus NC-EZH2 function in TNBC pathogenesis, we reveal that selective hyperactivation of H3K27me3 over NC-EZH2 not only promotes TNBC metastasis but also alters the metastatic landscape of TNBC. Using extensive in- vivo live animal imaging, we present conclusive evidence that peritoneal metastasis, particularly splenic metastasis of TNBC is governed by H3K27me3. Transcriptome analyses of hyperactive H3K27me3 cells lead us to discover Cytokeratin-14 (KRT14) as a new target of H3K27me3. Unlike classical H3K27me3 mediated suppression of gene expression, here; we observe that H3K27me3 enhances KRT14 transcription by attenuating the binding of transcriptional repressor Sp1 to its promoter. Further, loss of KRT14 significantly reduces TNBC migration, invasion and splenic metastasis. Finally, genetic ablation of EZH2 or pharmacological inhibition of EZH2 catalytic function by FDA approved drug tazemetostat (EPZ6438) robustly inhibits TNBC peritoneal metastasis. Altogether, our preclinical findings posit a rational insight for the clinical development of H3K27me3 inhibitor like tazemetostat as a targeted therapy against TNBC.

cancer biology↗

bioRxiv2020

Salinomycin inhibits epigenetic modulator EZH2 to enhance Death Receptors in Colon Cancer Stem Cells

Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumor cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotype such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.

cancer biology↗

bioRxiv2019

CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5

CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, CXCR4 signaling inhibitor drug Plerixafor has shown limited clinical success in cancer treatment. Therefore, CXCR4 signaling may not be the exclusive contributor to its pro-tumorigenic functions. In our continuous effort to understand the chemokine receptor signaling inhibition as cancer therapy, here we unexpectedly discovered that instead of its signaling, intracellular CXCR4 protein augments therapy resistance and pro-tumorigenic functions. Unbiased proteome profiler apoptosis array followed by immunoblot, FACS, real-time PCR and ChIP analyses demonstrate that CXCR4 promotes DR5 downregulation via modulating differential recruitment of transcription factors p53 and YY1 to its promoter. Surprisingly, inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, its loss compromised colon tumor growth in vivo. Finally, TCGA data mining and human patient sample data analysis showed CXCR4 and DR5 are inversely regulated in human cancers. Together, we showed evidence for the first time that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.

cancer biology↗