Research Area

My interest is in understanding the signal interplay between metabolic adaptation and stress kinase signaling in cancer cells under different tumor micro-environment conditions. Identification of proteins that are associated with signaling cross-talk will help to determine the therapeutic potential of such interaction. 

Our Lab Focus

• Mitochondrial Dynamics

• G-Protein Coupled Estrogen Receptor 

• Cell Migration and Actin Dynamics 

• Metabolic Regulation

• Circadian Rhythm 

GPER inhibits Branched chain amino acid metabolism

Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling, energy balance and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite BCAA’s importance in human health, our understanding of its metabolic regulation is limited. In our recent publication in FEBS letters, we presented evidence that G-protein coupled estrogen receptor (GPER) activation inhibits key BCAA metabolic regulatory enzyme, branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in Leucine, Isoleucine and Valine accumulation in the cells. Interestingly, GPER did not alter the BCKDK and PPM1K levels but activated the MAPK signalling and using gene silencing, we have identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling. 

General significance: To the best of our knowledge, we presented data for the first time that the direct involvement of hormonal receptor GPER regulating the BCAA metabolism by inhibiting key regulatory enzyme BCKDH through JNK signaling leading to the accumulation of BCAA in cells. The GPER-mediated regulation of BCAA metabolism is significant because both estrogen and BCAA have a significant impact on normal physiology and are directly linked to several disease conditions.

Anshu et al., FEBS letters 2025

GPER induces mitochondrial fission through p44/42 MAPK - Drp1 pathway

Understanding GPER biology in breast cancer is rather limited in compassion to the classic estrogen receptors. Mitochondrial dynamics play a critical role in determining cell survival and death under various microenvironmental conditions. We present evidence that GPER-induce mitochondrial fission in breast cancer cells. GPER mediated mitochondrial fission through activating Drp1 by phosphorylating S616 residue and down-regulates fusion proteins Mfn1 and Mfn2 levels. GPER-induced Drp1 activation mediated by p44/42 MAPK and inhibition of this signalling axis completely reverse the mitochondrial fission induced by GPER. Further, mitochondrial fission is required for GPER-induced cell death in breast cancer cells. To conclude, GPER induces mitochondrial fission through p44/42 MAPK - Drp1 signalling, and mitochondrial fission is critical for GPER-induced cell death in breast cancer cells. 

General significance: First time we report GPER's role in mitochondrial dynamics in cancer cells. Mitochondrial dynamics play a critical role in cancer progression including tamoxifen resistance. Exploring a detailed mechanistic understanding of GPER signalling may help to design new therapy for advanced cancers.

Rekha et al., Biochemical and Biophysical Research Communications 643 (2023) 16e23

 https://doi.org/10.1016/j.bbrc.2022.12.061 

Tamoxifen induces mitochondrial fusion during nutrition deprivation

The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Our recent work suggests that tamoxifen supports breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK signaling. Tamoxifen enhances mitochondrial fusion under nutrition-deprived conditions by suppressing Drp1 ser616 phosphorylation. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion by regulating stress kinase signaling during nutrition deprivation.

Vijaykumar et al., Cell Biology International (2022) 

https://doi.org/10.1002/cbin.11853