Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Mildred Acevedo-Duncan, Ph.D.

Committee Member

Ioannis Gelis, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Keywords

Cell Viability, Migration, Apoptosis, PKC-i, PKC-ζ

Abstract

Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%); 75% of the cases involve conventional clear cell RCC (ccRCC). The choice of treatments recommended for clear cell carcinoma and non-clear cell carcinoma include partial nephrectomy (Stage I), radical nephrectomy (Stages II and III), and chemotherapy (stage IV). Phosphatidylinositol-3-kinase (PI3K) inhibitors can be a viable candidate in the chemotherapy of ccRCC because the PI3K/Akt pathway is frequently activated in RCC. Hence, PI3K inhibitors like Alpelisib (BYL719) can be chosen as a treatment. In addition, aPKCs (PKC-ί and PKC ζ) are overexpressed in most cancer cells, and they play a central role in tumor progression and the metastasis of different types of cancers. Treatment of ccRCC metastatic clear cells with a combination of aPKC inhibitor ICA-1 and BYL 719 inhibits PKC-ί and it also causes the downstream inhibition of c-Myc. Inhibition of the aPKCs (PKC ί) also reduces the activation of other important proteins, such as Mitogen-Activated Protein Kinase Kinase (MEK) and extracellular signal-regulated kinase (ERK1/2). It is observed that treatment with ICA-1 disrupts the level of the aPKC-Akt1 association, which, in turn, reduces the activation of Akt1 through phosphorylation. ICA-1 treatment also disrupts the association between aPKC and c-Myc. The inhibition of aPKCs and other downstream effector proteins by combination therapy is more pronounced compared to a single therapy. These effects contribute to reduced cell growth, cell survival, and, eventually, the induction of apoptosis. The wound healing assay and the Boyden Chamber assay also suggested that there is decreased invasiveness of the cells when treated with the combination treatment. This can occur due to the inactivation of both ERK1/2 and Akt by the combination treatment. The decreased level of N-cadherin, p-vimentin, and vimentin and the increased level of E-cadherin confirm reduced malignancy. Therefore, implementing a combination of Alpelisib and an aPKC inhibitor is an effective approach to reducing cell proliferation, invasion, and resistance that eventually induces apoptosis.

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