Abstract:
Resistance to chemotherapeutic drugs is a major setback in cancer therapy, which leads to a high proportion of relapses and poor survival outcomes in cancer patients. Chemoresistance is frequently elicited by abnormal pre-mRNA alternative splicing, regulated by crucial kinases such as the serine-arginine protein kinase 1 (SRPK1). While SRPK1 has been implicated recently in chemoresistance in several tumours, the molecular mechanisms of this process are not known. In the present study, we aim to investigate in depth the role of SRPK1 (and other kinases from the same family) in chemoresistance across multiple cancers. We first generated two cisplatin (CDDP)-resistant cell lines (breast cancer CDDP-4R and colon cancer HCT-116-4R) and a docetaxel (DTX)-resistant (prostate cancer PC-3-5R) cell line by continuous exposure (over a period of 8 months) of PC-3, MDA-MB-231 and HCT-116 cells to sub-lethal, stepwise increasing concentrations of drugs. Subsequently, we evaluated how sensitivity to chemotherapeutic drugs measured by the MTT assay changes with SRPK1 inhibition using SPHINX31 in the three cell lines. Combining SPHINX31 with chemotherapeutic drugs significantly sensitizes the parental (sensitive) cell lines but less prominently the resistant cell lines. Immunoblotting showed that the level of SRPK1 in the parental (sensitive) MDA-MB-231 cells increased when treated with CDDP alone as well as in combination with SPHINX31. In resistant MDA-MB-231 cells, CDDP did not increase SRPK1 expression on its own but did so when combined with SPHINX31. In the parental (sensitive) HCT-116 colon cancer cells, both CDDP on its own and in combination with SPHINX31 decreased the expression of SRPK1, while in the resistant line, both treatments increased the expression. Finally, in the parental (sensitive) PC-3 prostate cancer cells, treatment with DTX alone or in combination with SPHINX31 decreased SRPK1 expression, while in the resistant PC-3 line, DTX on its own did not affect SRPK1 expression; however, when combined with SPHINX31, expression of SRPK1 decreased. This indicates that SRPK1 protein levels might be differentially regulated in various resistant cell lines and support the hypothesis that SRPK1 is involved in chemoresistance. Potentially, our future studies will reveal the role of SRPK1 in the development of chemoresistance in cancer cells and suggest a potential therapeutic avenue for overcoming chemotherapy resistance.
Audience Take Away Notes:
- Audience will be able to learn how to become chemoresistance in multiple types of cancer in experimental medicine
- Establishment models of acquired chemotherapeutic drugs resistance
- Generating experimental model related to chemoresistance
