Sib Sankar Roy

Altered fatty acid oxidation via CPT1A promotes epithelial‐to‐mesenchymal transition in ovarian cancer

Metabolic alterations are increasingly recognized as fundamental features of cancer. Recent studies have highlighted the involvement of altered fatty acid oxidation (FAO) at different stages of tumor development. As the rate‐limiting enzyme of FAO, CPT1 plays a crucial role in these metabolic adaptations in cancer cells. However, the regulation of CPT1 expression and activity in tumor cells still requires detailed investigation. Our studies reveal that CPT1A, a variant of CPT1, is significantly upregulated in ovarian cancer (OC) and correlates with poor prognosis. Inhibition of CPT1A, either by siRNA‐mediated knockdown or by etomoxir, reduces the migratory and invasive properties of the OC cells. CPT1A exerts these effects by modulating the expression of epithelial‐to‐mesenchymal transition (EMT)‐associated genes at transcriptional and protein levels. Growth factors such as transforming growth factor beta (TGFβ) are abundant in the tumor microenvironment and modulate the metabolic profile of tumors, thereby promoting EMT. Our findings demonstrate that TGFβ treatment increases the rate of FAO in ovarian cancer cells. Mechanistically, TGFβ mediates this effect by enhancing CPT1A expression and its enzymatic activity in OC cells through an AMPK‐dependent pathway. Additionally, we identified NRF2 as a potential transcriptional regulator of CPT1A within the context of TGFβ‐AMPK signaling. Finally, inhibiting CPT1A successfully attenuates TGFβ‐induced EMT in ovarian cancer cells. Cumulatively, our study underscores the role of CPT1A‐mediated FAO in facilitating ovarian cancer progression through TGFβ‐induced EMT.

A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions

Monocarboxylate transporters (MCTs) play an immense role in metabolically active solid tumors by regulating concentration-dependent transport of different important monocarboxylates including pyruvate and lactate and are encoded by the SLC16A family of genes. Given the vast array of functions, these transporters play in oncogenesis, our objective was to look into the association of MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8), and MCT4 (SLC16A3) with Epithelial ovarian cancer (EOC) pathophysiology by exploiting various publicly available databases and web resources. Few of the

Unveiling stem-like traits and chemoresistance mechanisms in ovarian cancer cells through the TGFβ1-PITX2A/B signaling axis

Ovarian cancer (OC) is the deadliest gynecological malignancy, having a high mortality rate due to its asymptomatic nature, chemoresistance, and recurrence. However, the proper mechanistic knowledge behind these phenomena is still inadequate. Cancer recurrence is commonly observed due to cancer stem cells which also show chemoresistance. We aimed to decipher the molecular mechanism behind chemoresistance and stemness in OC. Earlier studies suggested that PITX2, a homeobox transcription factor and, its different isoforms are associated with OC progression upon regulating different signaling pathways. Moreover, they regulate the expression of drug efflux transporters in kidney and colon cancer, rendering chemoresistance properties in the tumor cell. Considering these backgrounds, we decided to look for the role of PITX2 isoforms in promoting stemness and chemoresistance in OC cells. In this study, PITX2A/B has been shown to promote stemness and to enhance the transcription of ABCB1. PITX2 has been discovered to augment ABCB1 gene expression by directly binding to its promoter. To further investigate the regulatory mechanism of PITX2 gene expression, we found that TGFβ signaling could augment the PITX2A/B expression through both SMAD and non-SMAD signaling pathways. Collectively, we conclude that TGFβ1-activated PITX2A/B induces stem-like features and chemoresistance properties in the OC cells.

Oncogene‐mediated nuclear accumulation of lactate promotes epigenetic alterations to induce cancer cell proliferation

AbstractHomeobox gene families are associated with embryonic development and organogenesis. Pieces of evidence suggest that these Homeobox genes are also crucial in facilitating oncogenesis when mutated or overexpressed. Paired homeodomain transcription factor‐2 (PITX2), one of the members of this family, is involved in oncogenic regulation apart from its different development regulatory functions. PITX2 has been earlier shown to induce ovarian cancer cell proliferation through the activation of different signaling cascades. Increased cancer cell proliferation requires a constant supply of nutrients for both adenosine triphosphate and biomass synthesis, which is facilitated by altered cancer cell metabolism that includes enhanced glucose uptake and increased glycolytic rate. This present study highlights the involvement of PITX2 in enhancing the cellular glycolysis pathway in ovarian cancer cells through protein kinase B‐phosphorylation (phospho‐AKT). PITX2 expression correlates positively with that of the glycolytic rate‐determining enzyme, lactate dehydrogenase‐A (LDHA), in both high‐grade serous ovarian cancer tissues and common ovarian cancer cell lines. Interestingly, transient localization of enzymatically active LDHA in the nucleus was observed in PITX2‐overexpressed ovarian cancer cells. This nuclear LDHA produces higher concentrations of the glycolytic end product, lactate, which accumulates in the nuclear compartment resulting in decreased histone deacetylase (HDAC1/2) expression and increased histone acetylation at H3/H4. However, the mechanistic details of lactate–HDAC interaction are still elusive in the earlier reports. Our in silico studies elaborated on the interaction dynamics of lactate in the HDAC catalytic core through ligand‐binding studies and molecular dynamics simulation approaches. Blocking lactate production by silencing LDHA reduced cancer cell proliferation. Thus, PITX2‐induced epigenetic changes can lead to high cellular proliferation and increase the size of tumors in syngeneic mice as well. Taken together, this is the first report of its kind to show that the developmental regulatory homeobox gene PITX2 could enhance oncogenesis through enhanced glycolysis of tumor cells followed by epigenetic modifications.

SIRT6 promotes mitochondrial fission and subsequent cellular invasion in ovarian cancer

Ovarian cancer ranks fifth in terms of cancer mortality in women due to lack of early diagnosis and poor clinical management. Characteristics like high cellular proliferation, EMT and metabolic alterations contribute to oncogenicity. Cancer, being a “metabolic disorder,” is governed by various key regulatory factors like metabolic enzymes, oncogenes, and tumor suppressors. Sirtuins (SIRT1‐SIRT7) belong to the group of NAD+ deacetylase and ADP‐ribosylation enzymes that function as NAD+ sensors and metabolic regulators. Among sirtuin orthologs, SIRT6 emerges as an important oncogenic player, although its possible mechanistic involvement in ovarian cancer advancement is still elusive. Our data indicated a higher expression of SIRT6 in ovarian cancer tissues compared with the non‐malignant ovarian tissue. Further, we observed that overexpression of SIRT6 enhances glycolysis and oxidative phosphorylation in ovarian cancer cells. The energy derived from these processes facilitates migration and invasion through invadopodia formation by reorganization of actin fibers. Mechanistically, SIRT6 has been shown to promote ERK1/2‐driven activatory phosphorylation of DRP1 at serine‐616, which has an obligatory role in inducing mitochondrial fission. These fragmented mitochondria facilitate cell movement important for metastases. siRNA‐mediated downregulation of SIRT6 was found to decrease cellular invasion through compromised mitochondrial fragmentation and subsequent reduction in stress fiber formation in ovarian cancer cells. Thus, the present report establishes the impact of SIRT6 in the regulation of morphological and functional aspects of mitochondria that modulates invasion in ovarian cancer cells.