Monica Sosa

Introduction: Ovarian cancer (OC) is one of the most lethal gynecological malignancies.^1,2 Currently there are no diagnostic approaches to screen for early stage OC, with most cases being detected in the advanced stages (Stage III-IV).² Furthermore, once the disease has been diagnosed and treatment has begun the majority of patients develop multi-drug resistance (MDR), which causes relapse and chemotherapy failure.^1,2 Studies have found deregulation of ovarian cancer stem cells (CSC) contribute to the resistance to chemotherapy.^2,3 Specifically, a previous study on OC xenograft mouse models and OC cell lines found an upregulation of cluster of differentiation 44 (CD44) during the progression of OC, including acquisition of drug resistance.⁴ CD44 has been shown to enhance the expression of P-glycoprotein (P-gp), a product of the MDR1 gene and ABC1 transporter, known to generate drug resistance via pumping out cytotoxic drugs used in chemotherapy.⁵ With a better understanding of the mechanisms involved between CD44 and P-gp better therapeutic methods can be developed to improve outcomes.  Methods: A yeast two-hybrid system was used to evaluate the effect of CD44 mutations on P-gp function and expression. A high throughput siRNA ligase library screening method and a rapid in vitro test for P-gp function to select candidates for a P-gp-targeted E3 ligase.⁵ Results: The phosphorylated CD44 at Ser291 regulates P-gp by impeding its degradation by FBXO21, an orphan E3 ligase involved in the proteasome-mediated degradation of P-gp via ubiquitination.⁵ Although the exact mechanism of the inhibition of FBXO21 by CD44 in OC has not been studied there have been similar studies in human colorectal cancer cells that have illustrated the involvement of the MEK pathway in maintaining P-gp expression.^5,6,7 RSK1, an enzyme activated by the MEK pathway, induces self-ubiquitination of UBE2R1, a protein similar to FBOX21, involved in the degradation of P-gp.^6,7 It is possible that similar mechanisms are taking place in OC. Furthermore, studies in breast cancer cells have shown CD44 and ERM (Ezrin, Radixin and Moesin) influence P-gp-mediated MDR which lend a clue to the importance of the phosphorylated CD44 at Ser291, no longer bound to Ezrin.^5,8 Conclusion: It is clear that CD44 is playing an active role in inducing multi-drug resistance of ovarian cancer stem cells. The mechanistic interactions between CD44 and P-gp should be further explored in order to develop more targeted therapies that overcome the multi-drug resistance pathways currently in place in the ovarian cancer stem cells.

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5. Ravindranath AK, Kaur S, Wernyj RP, et al. CD44 promotes multi-drug resistance by protecting P-glycoprotein from FBXO21-mediated ubiquitination. Oncotarget. 2015;6(28):26308. http://www.ncbi.nlm.nih.gov/pubmed/26299618
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7. Katayama K, Fujiwara C, Noguchi K, Sugimoto Y. RSK1 protects P-glycoprotein/ABCB1 against ubiquitin–proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1. Scientific Reports. 2016;6:36134. https://search.proquest.com/docview/1899121199. doi: 10.1038/srep36134.
8. Pokharel D, Padula MP, Lu JF, Jaiswal R, Djordjevic SP, Bebawy M. The role of CD44 and ERM proteins in expression and functionality of P-glycoprotein in breast cancer cells. Molecules (Basel, Switzerland). 2016;21(3):290. http://www.ncbi.nlm.nih.gov/pubmed/26938523. doi: 10.3390/molecules21030290.