MSc in Botany with Plant Physiology and Biochemistry Specialization from The University of Burdwan, West Bengal, India
PhD in Biotechnology from Daegu University, Republic of Korea
Post-Doctoral: 2013-2016, Daegu University, Republic of Korea
Post-Dcotoral: 2016-2021, University of Minnesota, United States
RESEARCH, TEACHING, or OTHER INTERESTS
Agricultural and Biological Sciences, Biochemistry, Genetics and Molecular Biology, Cancer Research, Cell Biology
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Scopus Publications
Scopus Publications
Autophagy–Apoptosis Crosstalk in Cancer: Mechanisms, Signaling Pathways, and Therapeutic Targeting Dia Kakkar, Saloni Saxena, Utkarshita Dhawan, Naman Dosi, Charvi Khanna, Souren Paul Cancers, 2026 Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies.
Editorial: Activation of the cGAS-STING pathway by extra-nuclear DNA and its pharmacognostic modulation in human disease Preston M. McCourt, Charles A. Day, Souren Paul Frontiers in Pharmacology, 2025 potentially contributing to abnormal autoimmune responses (1). Significant efforts are underway to discover specific and effective cGAS-STING inhibitors as researchers aim to blunt the cGAS-STING pathway in auto-immune disorders. A recent study showed that flavonoids are effective against the cGAS-STING pathway (6) and, in addition, flavonoids are known to have strong antiinflammatory activities (7). This research collection also highlights efficacy of Licorice extract and polysaccharide from Glycyrrhiza uralensis against cGAS-STING pathway (8,9).. Conversely, cGAS-STING agonists may offer therapeutic benefits; a recent study demonstrated that activating this pathway induces IFN-β and primes CD8+ T cells to target tumor cells, highlighting its potential in cancer immunotherapy (108). However, some research indicates that the cGAS-STING pathway may also facilitate tumorigenesis and metastasis (119).Chen et. al., offered a comprehensive review on the role of cGAS-STING in liver diseases such as viral hepatits B and hepatocellular carcinoma (12). During viral hepatitis, cGAS-STING signaling, and cytokine synthesis play a pivotal role in the antiviral-activity of hepatocytes. In hepatocellular carcinoma, the cGAS-STING pathway is activated by DNA damage, leading to IFN-1 release which in turn activates tumor-specific CD8 + T cell and helps induce systemic tumor immunity. Moreover, the authors suggest that the activation of the cGAS-IRF3 pathway is positively correlated with the severity of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD).Another comprehensive review article by Ramos et. al. discusses the role of cGAS in various gastrointestinal (GI) diseases including inflammatory bowel disease (IBD) and in GI malignancy (13). The authors explain the contribution of cGAS-mediated autophagy activation on intestinal epithelial cell integrity and innate immunity responses. Interestingly, cGAS shows a contradictory role in GI-related cancers, showing both oncogenic and anti-oncogenic functions.Formatted: Font color: Red Formatted: Font color: Red Ramos et al. also discuss non-canonical activation of cGAS in various GI-related diseases (13).STING-independent activation of cGAS includes an interaction between cGAS and Beclin-1, autophagy activation and degradation of pathogenic DNA. On another note, cGAS mediated autophagy of micronuclei shows an interaction between cGAS and essential autophagy protein LC3. DNA damage in the nucleus can also trigger nuclear translocation of cGAS which inhibits homologous recombination of double strand breaks by interacting with PARP-1. The authors also summarize the potential antagonists and agonists used against cGAS in various cell lines and mouse models (13).In another cGAS-STING review, Colangelo et. al. explain the importance of cGAS-STING signaling in radiation therapy (14). The review gives an overview of the cGAS-STING pathway in tumor microenvironment after ionizing radiation exposure. DNA damage (nuclear or mitochondrial) from ionizing radiation releases to cytosol within a short period of time and activates cGAS-STING (14). The authors discuss the importance of immune cells in terms of STING activation, whether activated directly or by tumor-derived cGAMP (14)
Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis Souren Paul, Mark H. Kaplan, Dinesh Khanna, Preston M. McCourt, Anjan K. Saha, Pei-Suen Tsou, Mahek Anand, Alexander Radecki, Mohamad Mourad, Amr H. Sawalha, David M. Markovitz, Rafael Contreras-Galindo Nature Communications, 2022 Centromere defects in Systemic Sclerosis (SSc) have remained unexplored despite the fact that many centromere proteins were discovered in patients with SSc. Here we report that lesion skin fibroblasts from SSc patients show marked alterations in centromeric DNA. SSc fibroblasts also show DNA damage, abnormal chromosome segregation, aneuploidy (only in diffuse cutaneous (dcSSc)) and micronuclei (in all types of SSc), some of which lose centromere identity while retaining centromere DNA sequences. Strikingly, we find cytoplasmic “leaking” of centromere proteins in limited cutaneous SSc (lcSSc) fibroblasts. Cytoplasmic centromere proteins co-localize with antigen presenting MHC Class II molecules, which correlate precisely with the presence of anti-centromere antibodies. CENPA expression and micronuclei formation correlate highly with activation of the cGAS-STING/IFN-β pathway as well as markers of reactive oxygen species (ROS) and fibrosis, ultimately suggesting a link between centromere alterations, chromosome instability, SSc autoimmunity, and fibrosis.
GSTO1 confers drug resistance in HCT-116 colon cancer cells through an interaction with TNFαIP3/A20 Souren Paul, Monika Bhardwaj, Sun Kang International Journal of Oncology, 2022 The aim of the present study was to decipher the mechanism of glutathione-S-transferase Ω-1 (GSTO1)-induced drug resistance in colon cancer cells. Cisplatin is used widely as a therapeutic drug in cancer, but colon cancer is the most susceptible to acquired drug resistance. Autophagy is recognized as one of the contributors to drug resistance in cancers. Phase II detoxifying enzymes, such as GSTO1, serve important roles in autophagy-apoptosis cross talk. The present study revealed a novel interaction between GSTO1 and TNFα-induced protein 3/zinc-finger protein A20 (TNFαIP3/A20) as a prime target for cisplatin sensitization in drug-resistant cells. GSTO1 and ATP-binding cassette subfamily B member 1 (ABCB1) were both expressed at higher levels in multidrug-resistant (MDR) HCT-116 cells compared with the wild-type (WT) HCT-116 cells, suggesting they may serve vital roles in multidrug resistance. MDR cells showed autophagy induction, which is dependent on calcium signaling-dependent endoplasmic stress. In WT cells, the mitochondria-dependent pathway leads to apoptosis, which was not observed in MDR cells. The MDR conditions were mimicked by transfecting WT cells with the GSTO1-activation CRISPR plasmid, which induced autophagy. Similarly, MDR cells with GSTO1-knockdown (KD) CRISPR/Cas9 transfection showed reduced autophagy with increased apoptosis. These data revealed a potentially important role of GSTO1 in drug resistance. A GSTO1 pull-down assay detected TNFαIP3/A20 as a binding partner in MDR cells. The data suggested that the expression of TNFαIP3/A20 may be dependent on GSTO1 expression in MDR cells. Targeting either GSTO1 or TNFαIP3/A20 by CRISPR/Cas9 sensitized the MDR cells to cisplatin. GSTO1 and TNFαIP3/A20 dual-KD cells were more sensitive to cisplatin compared with single-gene KD cells. These data highlight the importance of the GSTO1-TNFαIP3/A20 interaction during drug resistance.
GSK3b-mediated expression of CUG-translated WT1 is critical for tumor progression Hisae Yoshitomi, Kun Y. Lee, Ke Yao, Seung Ho Shin, Tianshun Zhang, Qiushi Wang, Souren Paul, Eunmiri Roh, Joohyun Ryu, Hanyong Chen, Faisal Aziz, Abhijit Chakraborty, Ann M. Bode, Zigang Dong Cancer Research, 2021 The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box−/− WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. Significance: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.
Vitexin induces apoptosis by suppressing autophagy in multidrug resistant colorectal cancer cells Monika Bhardwaj, Hee Jun Cho, Souren Paul, Rekha Jakhar, Imran Khan, Seon-Jin Lee, Bo-Yeon Kim, Manigandan Krishnan, Tejinder Pal Khaket, Hee Gu Lee, Sun Chul Kang Oncotarget, 2018 Cancer treatment is limited due to the diverse multidrug resistance acquired by cancer cells and the collateral damage caused to adjacent normal cells by chemotherapy. The flavonoid compound vitexin exhibits anti-oxidative, anti-inflammatory and anti-tumor activity. This study elucidated the antitumor effects of vitexin and its underlying mechanisms in a multi-drug resistant human colon cancer cell line (HCT-116DR), which exhibits higher levels of multidrug-resistant protein 1 (MDR1) expression as compared with its parental cell line (HCT-116). Here, we observed that vitexin suppressed MDR-1 expression and activity in HCT-116DR cells and showed cytotoxic effect in HCT-116DR cells by inhibiting autophagy and inducing apoptosis in a concentration-dependent manner. Additionally, vitexin treatment caused cleavage of caspase-9 and caspase-3, and upregulated the expression of the pro-apoptotic proteins, BID and Bax. Moreover, the expression of autophagy-related proteins, such as ATG5, Beclin-1 and LC3-II, was markedly reduced by vitexin treatment. Furthermore, in vivo experiments showed that vitexin induced apoptosis and suppressed tumor growth in HCT-116DR xenograft model. These results revealed that vitexin induced apoptosis through suppression of autophagy in vitro and in vivo and provide insight into the therapeutic potential of vitexin for the treatment of chemo-resistant colorectal cancer.
Thymol elicits HCT-116 colorectal carcinoma cell death through induction of oxidative stress Anil Kumar Chauhan, Ashutosh Bahuguna, Souren Paul, Sun Chul Kang Anti Cancer Agents in Medicinal Chemistry, 2017 BACKGROUND Colon cancer is one of the most deadly and common carcinomas occurring worldwide and there have been many attempts to treat this cancer. The present work was designed in order to evaluate thymol as a potent drug against colon cancer. MATERIALS AND METHODS Cytotoxicity of thymol at different concentrations was evaluated against a human colon carcinoma cell line (HCT-116 cells). Fluorescent staining was carried out to evaluate the level of ROS as well as mitochondrial and DNA fragmentation and immunoblot analysis were performed to confirm apoptosis and mitoptosis. RESULTS AND CONCLUSION Results of the study demonstrated that thymol efficiently created an oxidative stress environment inside HCT-116 cells, a colorectal carcinoma cell line, through induction of ROS production along with intense damage to DNA and mitochondria, as observed through Hoechst and rhodamine 123 staining, respectively. Moreover, expression of PARP-1, p-JNK, cytochrome-C and caspase-3 proteins was up-regulated, suggesting HCT-116 cells underwent mitoptotic cell death. Therefore, thymol could be used as a potent drug against colon cancer due to its lower toxicity and prevalence in natural medicinal plants.
Herbacetin is a novel allosteric inhibitor of ornithine decarboxylase with antitumor activity Dong Joon Kim, Eunmiri Roh, Mee-Hyun Lee, Naomi Oi, Do Young Lim, Myoung Ok Kim, Yong-Yeon Cho, Angelo Pugliese, Jung-Hyun Shim, Hanyong Chen, Eun Jin Cho, Jong-Eun Kim, Sun Chul Kang, Souren Paul, Hee Eun Kang, Ji Won Jung, Sung-Young Lee, Sung-Hyun Kim, Kanamata Reddy, Young Il Yeom, Ann M. Bode, Zigang Dong Cancer Research, 2016
