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<p class="MsoNormal"><span style="font-size:13.5pt;font-family:"Arial",sans-serif;color:black;mso-ligatures:none"><img width="600" height="171" style="width:6.25in;height:1.7812in" id="Picture_x0020_13" src="cid:image001.png@01DBB2C1.05373CE0" alt="Dissertation Defense Announcement at the Cullen College of Engineering"></span><span style="font-size:13.5pt;font-family:"Arial",sans-serif;color:black;mso-ligatures:none"><o:p></o:p></span></p>
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<b><span style="font-size:18.0pt;color:#C8102E;mso-ligatures:none">The Role of c-Jun Signaling in Melanoma Cell Death Induced by Chemotherapeutic and Targeted Therapeutic Drugs<o:p></o:p></span></b></p>
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<b><span style="font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Shayne Sensenbach<o:p></o:p></span></b></p>
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<span style="font-size:13.5pt;mso-ligatures:none"><o:p> </o:p></span></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none">April 25, 2025; 1 p.m. to 2 p.m.
</span><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;mso-ligatures:none"><o:p></o:p></span></p>
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<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><b><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none"><a href="https://urldefense.com/v3/__https://zoom.us/j/98807734634?pwd=T9Ypv83KoaRou6bV8J6uRv6omwFQEj.1__;!!LkSTlj0I!AInuMm35rX6VskBk5cgrH3eUmY42gi9qiNkchTI6NdVxmxTNMU3L0aVru_LrjgYBuap-rg6BMS3of8imR68OxOX3Wd0$">Zoom
Link</a><o:p></o:p></span></b></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><b><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Meeting ID</span></b><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none">:
988 0773 4634<o:p></o:p></span></p>
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459490<o:p></o:p></span></p>
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<b><span style="font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Committee Chair:</span></b><span style="font-size:10.5pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none"><br>
</span><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Mehmet A. Orman, Ph.D.<o:p></o:p></span></p>
<p class="MsoNormal" align="center" style="text-align:center;line-height:150%"><b><span style="font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Committee Members:</span></b><span style="font-size:11.0pt;line-height:150%;font-family:"Arial",sans-serif;color:black;mso-ligatures:none"><br>
Chengzhi Cai, Ph.D. | Patrick Cirino, Ph.D. | Mehmet Sen, Ph.D. | <o:p></o:p></span></p>
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<span style="font-size:11.0pt;font-family:"Arial",sans-serif;color:black;mso-ligatures:none">Navin Varadarajan, Ph.D.</span><span style="font-size:10.5pt;font-family:"Arial",sans-serif;mso-ligatures:none"><o:p></o:p></span></p>
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<b><span style="font-family:"Arial",sans-serif;color:#C8102E;mso-ligatures:none">Abstract</span></b><span style="font-family:"Arial",sans-serif;color:#C8102E;mso-ligatures:none"><o:p></o:p></span></p>
<p class="MsoNormal" style="text-align:justify;line-height:160%"><span style="font-family:"Times New Roman",serif;color:black;mso-ligatures:none">Melanoma stands as an increasingly pressing health concern. Enhanced mitochondrial metabolism has been reported
in melanoma cells that survived treatment with traditional therapeutics, including cytidine analogs like gemcitabine (GEM). This suggests that chemotherapeutic drugs may have dual effects, promoting both cell survival and cell death, though the underlying
mechanisms remain unclear. More recently developed targeted therapeutics, specifically, BRAF and MEK inhibitors, have shown greater efficacy against melanoma than traditional chemotherapeutics. However, these drugs still fail to eradicate entire cancer cell
populations in most cases, and drug resistance commonly arises. The cellular responses to both these classes of drugs, including the mechanisms underlying drug tolerance and resistance, require further investigation.<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align:justify;line-height:160%"><span style="font-family:"Times New Roman",serif;color:black;mso-ligatures:none"> <o:p></o:p></span></p>
<p class="MsoNormal" style="text-align:justify;line-height:160%"><span style="font-family:"Times New Roman",serif;color:black;mso-ligatures:none">In our first project, we conducted proteomics analysis on GEM-treated melanoma cells and found a drug-induced activation
of DNA damage response and apoptosis, along with cell cycle arrest. Additionally, GEM treatment significantly altered protein networks related to mitochondrial ribosomal activity, the electron transport chain, and translation. Furthermore, we reported an upregulation
of the JNK/c-Jun network in connection with the apoptotic proteins. Co-treatment with a Jun N-terminal Kinase (JNK) inhibitor, JNK-IN-8 (JNKi), significantly increased cell survival, suggesting the involvement of c-Jun signaling in GEM-induced cell death.
Additionally, proteomics analysis revealed that JNKi downregulated apoptosis in co-treated cells, highlighting the potential role of the JNK/c-Jun network inhibition in chemotherapeutic tolerance.<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align:justify;line-height:160%"><span style="font-family:"Times New Roman",serif;color:black;mso-ligatures:none"> <o:p></o:p></span></p>
<p class="MsoNormal" style="text-align:justify;line-height:160%"><span style="font-family:"Times New Roman",serif;color:black;mso-ligatures:none">We used a similar strategy in our second project to characterize the response of melanoma cells to targeted therapeutics,
in addition to JNKi. Proteomics revealed cell cycle arrest in response to vemurafenib (VEM), a BRAF inhibitor, as well as upregulations in mitochondrial translation, mitochondrial respiration, and antioxidant defense pathways. We also observed modest activation
of c-Jun signaling in response to VEM treatment. Co-treatment with either VEM or cobimetinib (COB) plus JNKi led to synergistic killing compared to single treatment, suggesting an opposing role of the JNK/c-Jun pathway in this case. Collectively, our findings
bridge gaps in understanding how melanoma cells respond to chemotherapeutic and targeted therapeutic drugs by demonstrating the multifaceted effects of these agents, as well as the diverse role of c-Jun activation in each case.<o:p></o:p></span></p>
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<b><span style="font-family:"Arial",sans-serif;color:#C8102E;mso-ligatures:none"><img border="0" width="600" height="82" style="width:6.25in;height:.8541in" id="Picture_x0020_18" src="cid:image002.png@01DBB2C1.05373CE0" alt="Engineered For What's Next"></span></b><b><span style="font-family:"Arial",sans-serif;color:#C8102E;mso-ligatures:none"><o:p></o:p></span></b></p>
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