PP2A and tumor radiotherapy
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REVIEW
Open Access
PP2A and tumor radiotherapy Xiao Lei†, Na Ma†, Lehui Du†, Yanjie Liang, Pei Zhang, Yanan Han and Baolin Qu*
Abstract Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that serves as a key regulator of cellular physiology in the context of apoptosis, mitosis, and DNA damage responses. Canonically, PP2A functions as a tumor suppressor gene. However, recent evidence suggests that inhibiting PP2A activity in tumor cells may represent a viable approach to enhancing tumor sensitivity to chemoradiotherapy as such inhibition can cause cells to enter a disordered mitotic state that renders them more susceptible to cell death. Indeed, there is evidence that inhibiting PP2A can slow tumor growth following radiotherapy in a range of cancer types including ovarian cancer, liver cancer, malignant glioma, pancreatic cancer, and nasopharyngeal carcinoma. In the present review, we discuss current understanding of the role of PP2A in tumor radiotherapy and the potential mechanisms whereby it may influence this process. Keywords: Protein phosphatase 2A, Conventional tumor radiotherapy, DNA damage response, Radiosensitization effects
Introduction While mainstays of tumor treatment efforts, conventional radiotherapy and chemotherapy often yield unsatisfactory therapeutic outcomes [1–3]. These poor outcomes are generally linked to tumor cell multidrug resistance and resistance to ionizing radiation [4–6]. In addition, while these treatments are well-tailored to killing rapidly proliferating tumor cells, they generally fail to impact hypoxic and quiescent cells, ultimately resulting in treatment failure and tumor recurrence [7–9]. Understanding the mechanistic basis for tumor cell chemoresistance and radioresistance is thus vital. Interestingly, recent research evidence suggests that radiosensitization can be achieved by accelerating cell cycle progression in quiescent cells such that they become proliferative [10, 11]. Inhibiting proteins such as PP2A can drive quiescent tumor cells to enter mitosis, in turn potentially increasing tumor cell sensitivity to treatment [12, 13]. Inhibiting PP2A may therefore represent a * Correspondence: [email protected] † Xiao Lei, Na Ma and Lehui Du contributed equally to this work. The First Medical Center of Chinese PLA General Hospital, Department of Radiation Oncology, Beijing, P. R. China
valuable new approach to promoting tumor radiosensitization. In the present review, we discuss current research progress pertaining to the role of PP2A in the context of tumor radiotherapy.
The role of PP2A in radiation therapy
PP2A is a serine/threonine phosphatase that functions as a tumor suppressor gene [14]. It is a complex composed of a core enzyme and a regulatory subunit. The core enzyme (PP2AD) is a dimer comprised of a 36 kD catalytic subunit (PP2A c) and a 65 kD regulatory subunit (PR65 or subunit A). PP2A has three subunits, including subunit A and two subtypes of subunit C (α and β), with each of these subunits exhibiting distinct structural and catalytic acti
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