Resistance to platinum-containing chemotherapy in testicular germ cell tumors is associated with downregulation of the protein kinase SRPK1

Abstract

Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.

Figure 1

Representative examples of immunohistochemical staining for SRPK1. (A) Normal spermatogenesis (left) and carcinoma in situ (right). (a) Spermatogonium; (b) spermatocyte; (c) spermatid; (d) Sertoli cell; and (e) carcinoma in situ cell. (B) Chemotherapy-sensitive yolk sac tumor showing “very strong” SRPK1 staining. (C and D) Chemotherapy-resistant germ cell tumors (C, yolk sac tumor; D, choriocarcinoma) scored as “negative” to “weak” (heterogeneous), and “negative” (homogeneous), respectively. Original magnification, x 200.

Figure 2

Relative SRPK1 expression was compared between randomly selected germ cell tumors, chemorefractory germ cell tumors (DOD), poorprognosis high-dose-responsive, and standard chemotherapy-responsive germ cell tumors. (A) Pie chart showing the percentages of tumors with “negative” to “weak” SRPK1 staining (red), “intermediate” staining (yellow), and “strong” to “very strong” staining (green). (B) Box Whisker plots with cumulative SRPK1 scores. *Boxes encompass 25th to 75th percentiles, and the center lines within boxes show medians. Whiskers extend to the extreme values because all data points fell within 1.5 x the interquartile range. Median expression was compared by the two-sided Wilcoxon rank sum test in the randomly selected versus refractory (P < .0001) and high-dose-responsive group (P < .0001), and the standard chemotherapy-responsive versus the refractory (P < .0001) and high-dose-responsive group (P < .001).