Biology subjects

Lahiri, M.

Publications and source records attributed to Lahiri, M..

7 recordsLinked to original sources

bioRxiv2026

Api5 Regulates Genomic Stability and Chemotherapy Resistance in Cancer

Api5 is elevated in a number of cancers and is associated with many hallmarks of cancer, including resistance to apoptosis, immune escape, stemness, chemotherapy resistance, high proliferation, and cell-cycle dysregulation. In this study, we identified the DNA and chromatin-binding activities of Api5 in tumorigenic cells, as well as its association with genomic instability and chemotherapy resistance. Knockdown of Api5 resulted in reduced nuclear volume, DNA content, and chromosome number, and increased sensitivity to DNA damage. The survival of Api5-knockdown cells decreased following UV and cisplatin treatments due to the accumulation of damaged DNA and inefficient nucleotide excision repair. Interestingly, Api5 knockdown cells also exhibited low pChk1 levels following UV damage. Further, we confirmed the chemotherapy resistance phenotype in cancers with elevated Api5 levels, demonstrating that xenograft tumours with Api5 knockdown responded better to cisplatin, with significant tumour regression. SummaryApoptosis inhibitor 5 (Api5) contributes to chemotherapy resistance by conferring a survival advantage and promoting efficient DNA repair following genotoxic stress through regulation of Chk1 activation.

Cancer Biology↗

bioRxiv2026

Api5-FGF2 regulates the transformation of breast epithelial cells via PDK1/Akt and Ras/MAPK/ERK signalling

The equilibrium between cell death and cell division is crucial for maintaining tissue homeostasis in a multicellular organism. Apoptosis plays an essential role in preserving homeostasis and hence occurs in a coordinated manner. However, inhibition of apoptosis is one of the hallmarks of cancer. Apoptosis Inhibitor 5 (Api5), an anti-apoptotic protein, is upregulated in various cancers, including ovarian, bladder, cervical, and lung cancers. Studies have demonstrated that altered expression of Api5 leads to the transformation of non-tumorigenic breast epithelial cells. However, the mechanism regulating this process is not well-elucidated. Our study demonstrates that overexpression of Api5 increased FGF2 (Fibroblast Growth Factor 2) levels both at protein and transcript levels. We studied the mechanistic details of changes in morphology, proliferation, and polarity observed upon FGF2/FGFR1 deregulation in Api5-overexpressing cells. Deciphering the signalling mechanism underlying Api5-FGF2-mediated breast tumorigenesis revealed that the PDK1/Akt and Ras/MAPK/ERK pathways regulated multiple transformation phenotypes. PDK1/Akt enhanced proliferation and altered morphology during initial stages, whereas Ras/MAPK/ERK regulated polarity disruption, proliferation, and reduced apoptosis during later stages of morphogenesis. In conclusion, this study provides insights into the signalling mechanism regulating the transformation phenotypes associated with Api5 overexpression in a non-tumorigenic breast epithelial cell line.

cancer biology↗

bioRxiv2022

DNA damage leads to microtubule stabilisation through an increase in Golgi-derived microtubules

The site of nucleation strongly determines microtubule organisation and dynamics. The centrosome is a primary site for microtubule nucleation and organisation in most animal cells. In recent years, the Golgi apparatus has emerged as a site of microtubule nucleation and stabilisation. The microtubules originating from Golgi are essential for maintaining Golgi integrity post-Golgi trafficking, establishing cell polarity and enabling cell motility. Although the mechanism of nucleation and functional relevance of the Golgi-nucleated microtubule is well established, its regulation needs to be better studied. In this study, we report that DNA damage leads to aberrant Golgi structure and function accompanied by reorganisation of the microtubule network. Characterisation of microtubule dynamics post DNA damage showed the presence of a stable pool of microtubules resistant to depolymerisation by nocodazole and enriched in acetylated tubulin. Investigation of the functional association between Golgi dispersal and microtubule stability revealed that the Golgi elements were distributed along the acetylated microtubules. Microtubule regrowth assays showed an increase in Golgi-derived microtubule post DNA damage. Interestingly, reversal of Golgi dispersal reduces microtubule stabilisation. Altered intracellular trafficking resulting in mislocalisation of cell-cell junction proteins was observed post DNA damage. We propose that the increase in stable microtubules deregulates intracellular trafficking, resulting in cell polarity changes. This study would thus be the first to demonstrate the link between Golgi dispersal and microtubule reorganisation orchestrating changes in cell polarity.

cell biology↗

bioRxiv2022

Overexpression of TopBP1 leads to transformation with a TP53 mutation of non-tumorigenic breast epithelial cells

DNA topoisomerase II{beta} - binding protein 1 (TopBP1) is a mediator protein that regulates the cell cycle checkpoint signaling pathway. A plethora of studies suggests high TopBP1 levels are positively associated with various cancers. Although TopBP1 transcript, as well as protein expression levels, are high in breast cancers, its role in breast tumorigenesis is not yet explored. In our studies, we observed that TopBP1 levels are high in premalignant and malignant cells of the MCF10A cancer progression series compared to the non-tumorigenic MCF10A cells. In order to establish the role of TopBP1 in tumorigenesis, TopBP1 overexpression in non-tumorigenic MCF10A, and stable knock-down in malignant MCF10CA1a cells were performed and grown in Matrigel as breast spheroids. Overexpression of TopBP1 in MCF10A spheroids induced hyperproliferation, disruption of polarity and cell-cell junctions. Moreover, TopBP1 overexpressing 3D dissociated cells exhibited EMT-like phenotype and tumorigenic properties such as increased cell migration, invasion, colony formation capabilitiy and anchorage-independent growth, indicating acquisition of cellular transformation. Finally, we demonstrated TopBP1 overexpressing cells to form tumors in athymic mice thereby confirming their tumorigenic potential. We also confirmed that overexpression of TopBP1 led to a mutation in TP53 and other genomic insults. To summarise, we observed that ectopic expression of TopBP1 transforms MCF10A breast epithelial cells. These transformed cells harbour phenotypic and genotypic characteristics similar to that of malignant cells.

cancer biology↗

bioRxiv2021

Altered expression of Api5 affects breast carcinogenesis by modulating FGF2 signalling

Apoptosis or programmed cell death plays a vital role in maintaining homeostasis and, therefore, is a tightly regulated process. Deregulation of apoptosis signalling can favour carcinogenesis. Apoptosis inhibitor 5 (Api5), an inhibitor of apoptosis, is upregulated in cancers. Interestingly, Api5 is shown to regulate both apoptosis and cell proliferation. To address the precise functional significance of Api5 in carcinogenesis here we investigate the role of Api5 in breast carcinogenesis. Consistently, in-silico analysis revealed elevated levels of Api5 transcript in breast cancer patients which correlated with poor prognosis. Overexpression of Api5 in non-tumorigenic breast acinar cultures resulted in increased proliferation and cells exhibited a partial EMT-like phenotype with higher migratory potential and disruption in cell polarity. Furthermore, during acini development, the influence of Api5 is mediated via the combined action of FGF2 activated PDK1-Akt/cMYC signalling and Ras-ERK pathways. Conversely, Api5 knock-down downregulated FGF2 signalling leading to reduced proliferation and diminished in vivo tumorigenic potential of the breast cancer cells. Thus, taken together, our study identifies Api5 as a central player involved in regulating multiple events during breast carcinogenesis.

cancer biology↗

bioRxiv2021

ATR facilitates the degradation of Api5 through the ubiquitin-proteasome pathway via FBXW2 to regulate apoptosis upon DNA damage

Apoptosis inhibitor 5 (Api5) is an inhibitor of apoptosis, which is found to be upregulated in several cancers and promotes invasion as well as metastasis. Over-expression of Api5 is positively co-related with poor survival of cancers and inhibition of DNA damage induced apoptosis in cancerous cells. Acetylation at lysine 251 (K251) on Api5 facilitates the stability of the protein and thus functionally provides resistance to cancer cells against chemotherapeutic or anti-cancerous agents. However, the regulation of Api5 upon DNA damage is not yet known. In this study, we demonstrate that Api5 undergoes degradation following DNA damage via the ubiquitin-proteasome system. Upon DNA damage, ATR was observed to phosphorylate Api5 at serine 138 which led to the cytoplasmic localisation of Api5. The E3-ubiquitin ligase, SCF-FBXW2 ubiquitinates Api5 leading to its proteasomal degradation.

molecular biology↗

bioRxiv2020

Interplay between p300 and HDAC1 regulate acetylation and stability of Api5 to regulate cell proliferation

Api5, is a known anti-apoptotic and nuclear protein that is responsible for inhibiting cell death in serum-starved conditions. The only known post-translational modification of Api5 is acetylation at lysine 251 (K251). K251 acetylation of Api5 is responsible for maintaining its stability while de-acetylated form of Api5 is unstable. This study aimed to find out the enzymes regulating acetylation and deacetylation of Api5 and the effect of acetylation on its function. Our studies suggest that acetylation of Api5 at lysine 251 is mediated by p300 histone acetyltransferase while de-acetylation is carried out by HDAC1. Inhibition of acetylation by p300 leads to reduction in Api5 levels while inhibition of deacetylation by HDAC1 results in increased levels of Api5. This dynamic switch between acetylation and deacetylation regulate the localization of Api5 in the cell. This study also demonstrates that the regulation of acetylation and deacetylation of Api5 is an essential factor for the progression of the cell cycle.

molecular biology↗