Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum

Abstract

Ovarian cancer is the most lethal gynecological malignancy. Cisplatin and its derivatives are first-line chemotherapeutics, and their resistance is a major hurdle in successful ovarian cancer treatment. Understanding the molecular dysregulation underlying chemoresistance is important for enhancing therapeutic outcome. Here, we review two established pathways in cancer chemoresistance. p53 is a major tumor suppressor regulating proliferation and apoptosis, and its mutation is a frequent event in human malignancies. The PI3K/Akt axis is a key oncogenic pathway regulating survival and tumorigenesis by controlling several tumor suppressors, including p53. The interplay between these pathways is well established, although the oncogenic phosphatase PPM1D adds a new layer to this intricate relationship and provides new insights into the processes determining cell fate. Inhibition of the PI3K/Akt pathway by functional food compounds as an adjunct to chemotherapeutics may tip the balance in favor of apoptosis rather than survival, enhancing therapeutic efficacy, and reducing side effects.

Figure 1

Involvement of PPM1D in the regulation of CDDP sensitivity in ovarian cancer (OVCA) cells. (A) siRNA-mediated PPM1D downregulation–sensitized C13* cells, as evident by apoptotic cell count and poly (ADP-ribose) polymerase (PARP) cleavage, and enhanced sensitivity of OV2008 to CDDP-induced apoptosis in a concentration-dependent manner. OV2008 and C13* cells were incubated with PPM1D siRNA or control siRNA (0–400, 24 h), treated with CDDP (left panel: 0–10 μM, 12 h; right panel: 0–10 μM, 24 h), and PPM1D, PARP, cleaved PARP, and β-actin contents and apoptosis were assessed (n= 4). (B) Overexpression of PPM1D in OV2008 significantly decreased CDDP-induced apoptosis (P < 0.001), which was associated with decreased p-Ser³⁴⁵-Chk1 and p-Ser¹⁵-p53 contents (P < 0.01). OV2008 cells were transfected (1 μg, 24 h) with PPM1D cDNA or empty pCMV6-XL5 vector, treated with CDDP (0–10 μM, 24 h), and PPM1D, p-Ser³⁴⁵-Chk1, p-Ser¹⁵-p53, β-actin contents, and apoptosis were assessed (n= 3). ***P < 0.001 (versus respective CTL). From Ref. .

Figure 2

CDDP-induced, Chk1-mediated apoptosis is attenuated by PPM1D. PPM1D knockdown in C13* cells significantly upregulated p-Ser³⁴⁵-Chk1 and p-Ser¹⁵-p53 contents (P < 0.001). C13* cells were incubated with PPM1D siRNA or control siRNA (0–400 nM, 24 h), treated with CDDP (0–10 μM, 0–6 h), and PPM1D, p-Ser³⁴⁵-Chk1, p-Ser¹⁵-p53, and β-actin contents were assessed (n= 3). From Ref. .

Figure 3

Hypothetical model illustrating the possible involvement of FFCs in Akt and PPM1D stability in ovarian cancer cells in response to CDDP treatment. In chemoresistant cells, activated Akt enhances PPM1D stabilization and nuclear import, subsequently suppressing Chk1 and p53 activation, and the induction of proapoptotic gene transcription. FFCs directly inhibit PI3K, leading to suppressed Akt activation and to PPM1D degradation. The loss of inhibitory action of PPM1D on nuclear p-Chk1 and p-p53 contents ultimately results in the induction of apoptosis and CDDP sensitization.