BERKELEY, CA (UroToday.com) - Chemotherapeutic drug resistance is a major obstacle to the successful treatment of cancer. There are at least two previously characterized mechanisms of acquired resistance to taxanes: 1) some tumors contain α- and β-tubulin with an impaired ability to polymerize into microtubules and have an inherently slow rate of microtubule assembly that is normalized by the Taxol; and 2) amplification of membrane phosphoglycoproteins functions as drug-efflux pumps[2, 3, 4] Very recently, in studies of multi-drug resistance in PCa cells (22RV1), Liu et al. determined that a possible mechanism of tumor progression and drug resistance may involve the remarkably hypomethylated CpG islands on the ABCG2 promoter of CD117+/ABCG2+ cells and found they were hypomethylated.
Notably, the PI3K/Akt pathway plays a fundamental role in the regulation of cell growth, division, survival, and, when disarranged, tumorigenesis. Signaling of this pathway activates the Ser/Thr protein kinase Akt through phosphorylation, which in turn phosphorylates and regulates downstream effector proteins and promotes cell proliferation and survival.[6, 7] The MAP kinase pathway, similarly, plays a fundamental role in the regulation of cell proliferation, differentiation, and survival. Aberrant activation of this pathway through, for example a BRAF mutation is associated with tumorigenesis.[8, 9] Decreased activation of the MAP kinase pathway is associated with significant suppression of breast cancer cell growth in vitro and tumorigenesis in vivo. Additional data also suggest that the PI3K/Akt and MAP kinase pathways play important roles in drug resistance in human cancers.
Prostate cancer represents a highly heterogeneous tumor involving interaction among epithelial, endothelial, and stromal cellular components. Hence, the mechanism of drug resistance is likely to be a function of multiple factors. We focused on the PI3K/Akt and MAP kinase pathways and their effect on paclitaxel resistant DU-145 prostate cancer cell lines and their parental non-resistant cells. Our research attempted to identify whether these two signaling pathways are associated with mechanisms of drug resistance.
In Figure 1, for re-sensitizing DU145-TxR cells to paclitaxel, we assessed inhibitors of the PI3K/Akt and MAP kinase pathways. The DU145-TxR cells were treated with varying concentration of LY294002 and PD98059, the inhibitors of PI3K/Akt and MAP Kinase pathways respectively, for 24 hours. The expression of p-Akt and p-ERK was detected by western blot after treatment of both inhibitors (Figure 1a, 1b). The IC50 of paclitaxel in DU145-TxR cells was calculated at the same time with the treatment of LY294002 and PD98059 (Figure 1c, 1d). Data are shown as mean ±SD. Means p < 0.05 according to one way ANOVA and Holm-Sidak’s multiple comparisons with control group. Note the significant reversal of drug resistance
Regulation of chemotherapeutic sensitivity by PI3K/Akt and MAP Kinase pathway inhibitors is summarized in Figure 2. PI3K/Akt and MAPK pathway activation is associated with prostate cancer progression and resistance to chemotherapy. Inhibition of both pathways contributes to the re-sensitization of microtubule-based chemotherapy drugs. While pursuing mechanisms, we demonstrated a close association with Poly(ADP-ribose) Polymerase (PARP) cleavage. From a translational medicine perspective, inactivating the PI3K/Akt and MAP kinase pathways renders prostate cancer cells more sensitive to microtubule-targeting drugs such as paclitaxel, docetaxel, and vinblastine. Hence, combining such novel inhibitors of these two signaling pathways potentially may represent a more effective treatment for drug resistant prostate cancer.
Clearly, more in vitro and in vivo animal model work will be required to validate our observations as well as studies of other possible mechanisms related to epigenetic and genetic regulatory pathways to reverse paclitaxel resistance.[12, 13] Additionally, finding additional novel ways to reverse drug resistance for other key targeted chemotherapeutic anticancer drugs by identifying molecular mechanisms that may impede drug resistance should continue to be an imperative for FDA-approved anticancer drugs.
- Cabral F, Wible L, Brenner S, Brinkley BR. 1983. Taxol-requiring mutant of Chinese hamster ovary cells with impaired mitotic spindle assembly. J Cell Biol 97:30-9.
- Gupta RS. 1983. Taxol resistant mutants of Chinese hamster ovary cells: genetic biochemical, and cross resistance studies. J Cell Physiol 114:137-44.
- Horwitz SB, Cohen D, Rao S, Ringel I, Shen HJ, Yang CP. 1993. Taxol: mechanisms of action and resistance. J Natl Cancer Inst Monogr:55-61.
- Zhu MM, Tong JL, Xu Q, Nie F, Xu XT, Xiao SD, Ran ZH. 2012. Increased JNK1 signaling pathway is responsible for ABCG2-mediated multidrug resistance in human colon cancer. PLoS One 7:e41763.
- Liu T, Xu F, Du X, Lai D, Liu T, Zhao Y, Huang Q, Jiang L, Huang W, Cheng W, Liu Z. 2010. Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1. Mol Cell Biochem 340:265-73.
- Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. 2005. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988-1004.
- Vivanco I, Sawyers CL. 2002. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489-501.
- Dhillon AS, Hagan S, Rath O, Kolch W. 2007. MAP kinase signalling pathways in cancer. Oncogene 26:3279-90.
- Roberts PJ, Der CJ. 2007. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291-310.
- Cipriano R, Miskimen KL, Bryson BL, Foy CR, Bartel CA, Jackson MW. 2014. Conserved Oncogenic Behavior of the FAM83 Family Regulates MAPK Signaling in Human Cancer. Mol Cancer Res 12:1156-65.
- Pritchard AL, Hayward NK. 2013. Molecular pathways: mitogen-activated protein kinase pathway mutations and drug resistance. Clin Cancer Res 19:2301-9
- O'Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, O'Connor D, O'Connor R, Devery A, Corcoran C, Rani S, O'Driscoll L, Fitzpatrick JM, Watson RW. 2011. Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer 10:126.
- Seruga B, Ocana A, Tannock IF. 2011. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol 8:12-23.
Robert W. Veltri, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Associate Professor of Urology and Oncology
The Brady Urological Institute
The Johns Hopkins University School of Medicine
Department of Urology
Baltimore, MD USA