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Student Research

Student News and Views

October 2014

Lysosomal protease inhibitor helps tumor cells deal with stress
Reported by: Jennifer L. DeLeon, Ph.D. Candidate Molecular and Cellular Biology (MCB)

Squamous cell carcinoma antigen, or SCCA, was identified as a serum biomarker in several cancer types including cervical, lung, head and neck, and liver. However, the mechanism by which upregulation of SCCA contributes to tumorigenesis has been poorly understood. Recent work in the laboratory of Dr. Wei-Xing Zong showed that SCCA overexpression is associated with poorly differentiated and aggressive cancers of the breast, colon and pancreas. In normal tissue, SCCA functions as a protease inhibitor to block cytosolic leakage of lysosomal proteases and promote cell survival in the event of lysosomal damage. MCB alum Dr. Namratha Sheshadri and colleagues uncovered a tumorpromoting role of SCCA, which was recently published in Cancer Research. Dr. Sheshadri discovered that the upregulation of SCCA promotes the unfolded protein response and activation of pro-inflammatory signaling through the cytokine IL-6 in cell lines and a mouse model of mammary tumorigenesis.

  Figure 1: SCCA promotes EMT
  Figure 1

To study the tumor promoting function of SCCA, Sheshadri et al. overexpressed SCCA in the “normal” non-neoplastic human breast epithelial cell line MCF10A. Upon SCCA overexpression, they observed phenotypic changes resembling epithelial to mesenchymal transition (EMT); a change of cultured cells from a cobblestone-like monolayer to a spindle morphology (Figure 1). Likewise, transcription analysis showed an increase in EMT promoting markers like ZEB1 and vimentin, and the loss of epithelial markers like E-cadherin. SCCA overexpression leads to increased migration, anchorage independent colony formation, and growth factor autonomous cell proliferation and survival.

To elucidate the molecular mechanism for the cellular EMT like phenotype, Sheshadri screened several EMTpromoting growth factors and identified a significant increase in IL-6 transcription and secretion in SCCA expressing cells. Interestingly, pharmacological inhibition or genetic knockdown of IL-6 abrogated several of the transformation phenotypes induced by SCCA. IL-6 has been well appreciated as a potent cytokine for cell signaling, inflammation, and tumorigenesis, however, the question still remained, how does SCCA promotes IL-6 expression?

In a previous study, SCCA overexpression was shown to block lysosomal and proteasomal protein turnover, thus disrupting normal protein homeostasis. Sheshadri hypothesized that SCCA may potentiate the build-up of misfolded and ubiquitinated proteins and trigger the cellular stress response termed the unfolded-protein response (UPR). Indeed, SCCA transformed cells have increased levels of several UPR markers and display a chronic but nonlethal endoplasmic reticulum stress response. By genetic knockdown of these ER stress receptors, Sheshadri demonstrated a decrease in IL-6 transcription. Thus, the impaired protein degradation caused by elevated SCCA expression may lead to UPR, which has been implicated in pro-inflammatory response in numerous human diseases including cancer.

This work establishes an important example where disruption of protein homeostasis can contribute to EMT and tumorigenesis via the unfolded protein response. Importantly, it also identifies the Achilles heel for tumors that exhibit high expression of SCCA such that they are sensitized to ER stress-inducing pharmacological agents; and thus may be an advantageous therapeutic target in human cancers.

Dr. Namratha SheshadriTo read the full article please see:
Sheshadri, N., et al. SCCA1/SERPINB3 Promotes Oncogenesis and Epithelial-Mesenchymal Transition via the Unfolded Protein Response. Cancer Research. 2014 Sep 11.

Author Highlight: Dr. Namratha Sheshadri, Ph.D.
Namratha graduated from Stony Brook University with a Ph.D. in Molecular and Cell biology from the laboratory of Dr. Wei-Xing Zong in August 2014. Her thesis research uncovered the cellular mechanism of lysosomal protease inhibitor SCCA to initiate breast cancer tumorigenesis. Namratha recently obtained a post-doctoral position at the National Cancer Institute (NCI). Aside from scientific research, Namratha’s interests include bird watching, gardening, hiking and traveling.

 

 


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